Opioid agonist /antagonist combinations

ABSTRACT

The invention is directed in part to oral dosage forms comprising a combination of an orally analgesically effective amount of an opioid agonist and an orally active opioid antagonist, the opioid antagonist being included in a ratio to the opioid agonist to provide a combination product which is analgesically effective when the combination is administered orally, but which is aversive in a physically dependent subject. Preferably, the amount of opioid antagonist included in the combination product provides at least a mildly negative, “aversive” experience in physically dependent addicts (e.g., precipitated abstinence syndrome).

[0001] This application is a continuation application of U.S.Provisional Application Ser. No. 60/068,480 filed Dec. 22, 1997, herebyincorporated by reference.

[0002] Opioids, also known as opioid agonists, are a group of drugs thatexhibit opium or morphine-like properties. The opioids are employedprimarily as moderate to strong analgesics, but have many otherpharmacological effects as well, including drowsiness, respiratorydepression, changes in mood and mental clouding without a resulting lossof consciousness. Opioids act as agonists, interacting withstereospecific and saturable binding sites in the brain and othertissues. Endogenous opioid-like peptides are present particularly inareas of the central nervous system that are presumed to be related tothe perception of pain; to movement, mood and behavior, and to theregulation of neuroendocrinological functions. Opium contains more thantwenty distinct alkaloids. Morphine, codeine and papaverine are includedin this group.

[0003] By the middle of the nineteenth century, the use of purealkaloids such as morphine rather than crude opium preparations began tospread throughout the medical world. Parenteral use of morphine tendedto produce a more severe variety of compulsive drug use. The problem ofaddiction to opioids stimulated a search for potent analgesics thatwould be free of the potential to produce addiction. By 1967,researchers had concluded that the complex interactions amongmorphine-like drugs, antagonists, and what was then called “mixedagonist-antagonist” could best be explained by postulating the existenceof more than one type of receptor for opioids and related drugs. Withthe advent of new totally synthetic entities with morphine-like actions,the term “opioid” was generally retained as a generic designation forall exogenous substances that bind stereo-specifically to any of severalsubspecies of opioid receptors and produce agonist actions.

[0004] The potential for the development of tolerance and physicaldependence with repeated opioid use is a characteristic feature of allthe opioid drugs, and the possibility of developing psychologicaldependence (i.e., addiction) is one of the major concerns in the use ofthe treatment of pain with opioids, even though iatrogenic addiction israre. Another major concern associated with the use of opioids is thediversion of these drugs from the patient in pain to another(non-patient) for recreational purposes, e.g., to an addict.

[0005] The overall abuse potential of an opioid is not established byany one single factor. Instead, there is a composite of factors,including, the capacity of the drug to produce the kind of physicaldependence in which drug withdrawal causes sufficient distress to bringabout drug-seeking behavior; the ability to suppress withdrawal symptomscaused by withdrawal from other agents; the degree to which it induceseuphoria similar to that produced by morphine and other opioids; thepatterns of toxicity that occur when the drug is dosed above its normaltherapeutic range; and physical characteristics of the drugs such aswater solubility. Such physical characteristics may determine whetherthe drug is likely to be abused by the parenteral route.

[0006] In the United States, the effort to control the compulsive druguser includes efforts to control drug availability by placingrestrictions on the use of opioids in the treatment of pain ofcompulsive drug users. In practice, the physician is often faced with achoice of administering potent opioid analgesics even to persons whoseem predisposed to develop psychological dependence, i.e., addiction,on such drugs. In view of this problem, it has been recommended thatthese patients should not be given an opioid when another drug without apotential for abuse will suffice; and further that these patients shouldnot be permitted to self-administer such drugs parenterally and shouldonly be given a few days'supply at a time.

[0007] At least three basic patterns of opioid use and dependence havebeen identified. The first involves individuals whose drug use begins inthe context of medical treatment and who obtain their initial suppliesthrough, e.g., physicians. Another pattern begins with experimental or“recreational” drug use and progresses to more intensive use. A thirdpattern involves users who begin in one or another of the preceding waysbut later switch to oral opioids such as methadone, obtained fromorganized addiction treatment programs.

[0008] Tolerance refers to the need to increase the dose of opioid overa period of time in order to achieve the same level of analgesia oreuphoria, or the observation that repeated administration of the samedose results in decreased analgesia, euphoria, or other opioid effects.It has been found that a remarkable degree of tolerance develops to therespiratory depressant, analgesic, sedative, emetic and euphorigeniceffects of opioids. However, the rate at which this tolerance maydevelop in either an addict or in a patient requiring treatment of pain,depends on the pattern of use. If the opioid is used frequently, it maybe necessary to increase the dose. Tolerance does not develop equally orat the same rate to all the effects of opioids, and even users who arehighly tolerant to respiratory depressant effects continue to exhibitmiosis and constipation. Tolerance to opioids largely disappears whenthe withdrawal syndrome has been completed.

[0009] Physical dependence may develop upon repeated administrations orextended use of opioids. Physical dependence is gradually manifestedafter stopping opioid use or is precipitously manifested (e.g., within20 minutes) after administration of a narcotic antagonist (referred to“precipitated withdrawal”). Depending upon the drug to which dependencehas been established and the duration of use and dose, symptoms ofwithdrawal vary in number and kind, duration and severity. The mostcommon symptoms of the withdrawal syndrome include anorexia, weightloss, pupillary dilation, chills alternating with excessive sweating,abdominal cramps, nausea, vomiting, muscle spasms, hyperirritability,lachrymation, rinorrhea, goose flesh and increased heart rate.Abstinence syndrome typically begins to occur 24-48 hours after the lastdose, and the syndrome reaches its maximum intensity about the third dayand may not begin to decrease until the third week.

[0010] Psychological dependence (i.e., addiction) on opioids ischaracterized by drug-seeking behavior directed toward achievingeuphoria and escape from, e.g., psychosocioeconornic pressures. Anaddict will continue to administer opioids for non-medicinal purposesand in the face of self-harm.

[0011] Pharmacologically, opioid antagonists typically block or reverseall of the effect of opioid agonists. One use of opioid antagonists isas a once-a-day treatment of naltrexone to block euphoric effects thatmight be otherwise obtained upon administration of opioids to addicts.Small doses of opioid antagonists have been used to determine whetherindividuals are physically dependent on opioids. Most commonly, opioidantagonists are used to reverse the effects of opoids on individuals whohave overdosed on opioid agonist drugs.

[0012] There have previously been attempts in the art to control theabuse potential associated with opioid analgesics. Typically, aparticular dose of an opioid analgesic is more potent when administeredparenterally as compared to the same dose administered orally.Therefore, one popular mode of abuse of oral medications involves theextraction of the opioid from the dosage form, and the subsequentinjection of the opioid (using any “suitable” vehicle for injection) inorder to achieve a “high.” Attempts to curtail abuse have thereforetypically centered around the inclusion in the oral dosage form of anopioid antagonist which is not orally active but which willsubstantially block the analgesic effects of the opioid if one attemptsto dissolve the opioid and administer it parenterally.

[0013] For example, the combination of pentazocine and naloxone has beenutilized in tablets available in the United States, commerciallyavailable as Talwin®Nx from Sanofi-Winthrop. Talwin®Nx containspentazocine hydrochloride equivalent to 50 mg base and naloxonehydrochloride equivalent to 0.5 mg base. Talwin®Nx is indicated for therelief of moderate to severe pain. The amount of naloxone present inthis combination has no action when taken orally, and will not interferewith the pharmacologic action of pentazocine. However, this amount ofnaloxone given by injection has profound antagonistic action to narcoticanalgesics. Thus, the inclusion of naloxone is intended to curb a formof misuse of oral pentazocine which occurs when the dosage form issolubilized and injected. Therefore, this dosage has lower potential forparenteral misuse than previous oral pentazocine formulations. However,it is still subject to patient misuse and abuse by the oral route, forexample, by the patient taking multiple doses at once.

[0014] Sunshine, et al. “Analgesic Efficacy of Pentazocine Versus aPentazocine-Naloxone Combination Following Oral Administration”, Clin.J. Pain, 1988:4:35-40, reported on the effect of the addition of 0.5 mgnaloxone on the analgesic efficacy of pentazocine 50 mg. The combinationwas found to be significantly less efficacious than pentazocine for thesum of the pain intensity difference (SPID), and for relief and painintensity difference (PID) at the fourth hour. For patients withmoderate baseline pain, the combination produced significantly less painrelief than pentazocine for SPID and for relief and PID at hours 3 and4. In patients with severe baseline pain, there was no significantdifference found between pentazocine and the combination of pentazocineplus naloxone.

[0015] Wang, et al. “Crossover and Parallel Study of Oral Analgesics”,J. Clin Pharmacol 1981; 21:162-8, studied the combination of naloxone0.25 mg and Percodan® (composed of 4.5 mg oxycodone HCl, oxycodoneterephthalate 0.28 mg, aspirin 224 mg, phenacetin 160 mg, and caffeine32 mg) compared to Percodan® alone, and placebo in a crossover study ofpatients with chronic pain. The combination had lower mean scores thanPercodan® alone for most of the analgesic hourly parameters in the laterhours of the trial. However, for the summary variables, the combinationshowed no significant difference from either placebo or Percodan®.

[0016] A fixed combination of buprenorphine and naloxone was introducedin 1991 in New Zealand (Temgesic®Nx, Reckitt & Colman) for the treatmentof pain.

[0017] A fixed combination therapy comprising tilidine (50 mg) andnaloxone (4 mg) has been available in Germany for the management ofsevere pain since 1978 (Valoron®N, Goedecke). The rationale for thecombination of these drugs is effective pain relief and the preventionof tilidine addiction through naloxone-induced antagonisms at themorphine receptor.

[0018] U.S. Pat. No. 3,773,955 (Pachter, et al.) described orallyeffective analgetic compositions which upon parenteral administration donot produce analgesia, euphoria, or physical dependence, and therebyprevent parenteral abuse of the analgetic agents. Such compositionscontained from about 0.1 mg to about 10 mg naloxone per analgetic oraldose. This reference was not concerned with oral abuse of opioids.

[0019] U.S. Pat. No. 3,493,657 (Lewenstein, et al.) describedcompositions comprising naloxone and morphine or oxymorphone, whichcompositions were said to provide a strong analgesic effect without theoccurrence of undesired side effects such as hallucinations.

[0020] U.S. Pat. No. 4,457,933 (Gordon, et al.) described a method fordecreasing both the oral and parenteral abuse potential of stronganalgetic agents such as oxycodone, propoxyphene and pentazocine, bycombining an analgesic dose of the opioid with naloxone in a specific,relatively narrow range. Oxycodone-naloxone compositions having a ratioof 2.5-5:1 parts by weight and pentazocine-naloxone compositions havinga ratio of 16-50:1 parts by weight were preferred. The dose of naloxonewhich was to be combined with the opioid is stated to substantiallyeliminate the possibility of either oral or parenteral abuse of theopioid without substantially affecting the oral analgesic activitythereof.

[0021] U.S. Pat. No. 4,582,835 (Lewis) describes a method of treatingpain by administering a sublingually effective dose of buprenorphinewith naloxone. Lewis describes dosage ratios of naloxone tobuprenorphine from 1:3 to 1:1 for parenteral administration, and from1:2 to 2:1 for sublingual administration.

[0022] It has been increasingly recognized in the art that oral opioidformulations are not only being abused by the parenteral route, but alsovia the oral route when the patient or addict orally self-administersmore than the prescribed oral dose during any dosage interval. There istherefore a need for the development of a formulation for the treatmentof pain which is administrable orally and which provides a lowerpotential for oral abuse.

[0023] To the inventors'knowledge, a ratio of opigid agonist to opioidantagonist which would be analgesically effective when the combinationis administered orally, but which is aversive in a physically dependentsubject has not been recognized to date.

OBJECTS AND SUMMARY OF THE INVENTION

[0024] It is an object of the invention to provide an oral dosage formof an opioid analgesic which is subject to less abuse potential via theoral route than prior commercially available dosage forms.

[0025] It is a further object of the present invention to provide anoral dosage form of an opioid analgesic and method which providestherapeutic analgesia and which also provides a negative, “aversive”experience when a large amount of the opioid, e.g., about 2-3 times theusually prescribed dose, is taken by or administered to a physicallydependent subject.

[0026] It is a further object of the present invention to provide anoral dosage form of an opioid analgesic and a method for providingtherapeutic analgesia in a manner which is not as positively reinforcingin non-physically dependent subjects taking more than the usuallyprescribed dose, e.g., about 2-3 times the usually prescribed dose ofthe opioid, as compared to the same amount of opioid without theantagonist.

[0027] It is a further object of the invention to provide a method oftreating pain in human patients with an oral dosage form of an opioidanalgesic while reducing the oral abuse potential of dosage form.

[0028] It is a further object of the invention to provide a method ofmanufacturing an oral dosage form of an opioid analgesic such that ithas less oral abuse potential.

[0029] The above objects and others are achieved by the presentinvention, which is directed in part to the surprising finding thatthere exists a ratio of opioid antagonist to opioid agonist (analgesic)which is analgesically effective when the combination is administeredorally, but which is aversive in a physically dependent subject. To theinventor's knowledge, this was not even considered by those skilled inthe art, e.g., an addictionologist, analgesiologist, a clinicalpharmacologist. It is surprising that one combination product (ofcombined antagonist/agonist) could in essence be therapeutic to onepopulation (patients in pain), while being unacceptable (aversive) in adifferent population (e.g., physically, dependent subjects) whenadministered at the same dose or at a higher dose than the usuallyprescribed dosage, e.g., about 2-3 times the usually prescribed dose ofthe opioid.

[0030] The present invention is directed in part to an oral dosage formcomprising an orally analgesically effective amount of an opioid agonistand an opioid antagonist in a ratio which maintains analgesic efficacyby the opioid analgesic but which may decrease analgesia somewhat asassessed by direct measurement in patients or by the use of one or moresurrogate measures of opioid efficacy (analgesia) in human subjects.Surrogate measures of opioid efficacy (analgesia) include sedation,respiratory rate and/or pupil size (via pupillometry), and visualanalogue scale (“VAS”) for “drug effect”. Such surrogate measures areaffected in a direction which indicates reduced opioid effect, ascompared to the same dose of opioid without the concomitant dose ofopioid antagonist.

[0031] In certain preferred embodiments where the opioid is hydrocodoneand the antagonist is naltrexone, the oral dosage form includeshydrocodone in the form of its bitartrate salt and naltrexone in theform of its hydrochloride salt.

[0032] In certain preferred embodiments where the opioid is hydrocodoneand the antagonist is naltrexone, the ratio of naltrexone to hydrocodoneis preferably from about 0.03 - 0.27:1 by weight, and more preferablyfrom about 0.05-0.20:1 by weight.

[0033] The present invention is directed to a method of preventing oralabuse of an oral opioid formulation by a subject, comprising preparingan oral dosage form which comprises an orally analgesically effectiveamount of an opioid agonist and an opioid antagonist in a ratio whichmaintains analgesic efficacy by the opioid analgesic but which maydecrease analgesia somewhat as assessed by direct measurement inpatients or by the use of one or more surrogate measures of opioideffect in human subjects. When the oral dosage form is taken by aphysically dependent subject at a relatively large dosage, e.g., about2-3 times the usually prescribed dose, that use is aversive in aphysically dependent human subject and preferably not as positivelyreinforcing as the opioid (ingested alone) in a non-physically dependenthuman subject.

[0034] The present invention is also directed to a method of treatment,comprising orally administering an orally analgesically effective amountof an opioid agonist together with an opioid antagonist in a ratio whichmaintains analgesic efficacy by the opioid analgesic but which maydecrease analgesia somewhat by direct measurement in patients or by theuse of one or more surrogate measures of opioid effect in humansubjects.

[0035] The present invention is further directed in part to oral dosageforms comprising a combination of an orally analgesically effectiveamount of an opioid agonist and an orally active opioid antagonist, theopioid antagonist being included in an amount (i) which does not cause areduction in the level of analgesia elicited from the dosage form uponoral administration to a non-therapeutic level and (ii) which providesat least a mildly negative, “aversive” experience in physicallydependent subjects (e.g., precipitated abstinence syndrome) when thesubjects attempt to take at least twice the usually prescribed dose at atime (and often 2-3 times that dose or more), as compared to acomparable dose of the opioid without the opioid antagonist present.Preferably, the amount of naltrexone included in the oral dosage form isless positively reinforcing (e.g., less “liked”) to a non-physicallydependent opioid addict than a comparable oral dosage form without theantagonist included. Preferably, the formulation provides effectiveanalgesia when orally administered.

[0036] For purposes of the present invention, the phrase “which maydecrease analgesia somewhat as assessed by direct measurement inpatients or by the use of one or more surrogate measures of opioidanalgesic efficacy in human subjects” means that the patient in pain mayor may not appreciably notice the difference between the formulationadministered in accordance with the invention (i.e., combination ofopioid agonist/antagonist) and a similar formulation which includes thesame dose of opioid agonist without the opioid antagonist, but willobtain an analgesic effect from the combination. The pharmacodynamiceffect (analgesia) of the formulations administered in accordance withthe invention can be described by means of, for example, scores from ananalgesic questionnaire reported by the patients at serial timesfollowing administration of the dosage form. Summary measures ofanalgesia include the sum of pain intensity difference (SPID) and totalpain relief (TOTPAR).

[0037] In certain preferred embodiments, the amount of opioid antagonistincluded in the dosage form may cause a clinically significant reductionin the level of analgesia elicited from the dosage form upon oraladministration, e.g., as measured by surrogate measures such as a VisualAnalogue Scale (“VAS”) for “drug effect”. In other embodiments, theamount of opioid antagonist included in the oral dosage form may cause anoticeable reduction in the level of analgesia elicted from the dosageform upon oral administration, but does not reduce the level ofanalgesia provided to a subtherapeutic level.

[0038] Preferably, the amount of antagonist included in the oral dosageform is less positively reinforcing (e.g., less “liked”) by anon-physically dependent opioid subject than a comparable oral dosageform without the antagonist included.

[0039] The present invention is also directed to a method of preparingan oral dosage form of an opioid analgesic intended for the treatment ofpain in human patients in a manner which minimizes the likelihood oforal abuse of the dosage form, combining an orally analgesicallyeffective amount of an opioid agonist together with an opioid antagonistin a ratio which maintains analgesic efficacy by the opioid analgesicbut which may decrease analgesia somewhat by direct measurement inpatients or by the use of one or more surrogate measures of analgesia inhuman subjects. In certain embodiments, the combination when orallyadministered-provides a clinically significant reduction in the level ofanalgesia elicited from the dosage form upon oral administration (ascompared to the same dose of opioid alone), and provides at least amildly negative, “aversive” experience in a physically dependent subject(e.g., precipitated abstinence syndrome) when the subject takes morethan the usually prescribed or usual dose of opioid. The subject may be,for example, an addict who attempts to achieve euphoria (a “high”) bytaking more than (e.g., at least 2-3 times) the usually prescribed doseat a time. The amount of opioid antagonist included in the dosage formmay or may not cause a noticeable reduction in the level of analgesiaelicited from the dosage form upon oral administration, e.g., asmeasured by pharmacodynamic parameters such as a Visual Analogue Scale(“VAS”) for drug effect, but preferably allows the dosage form tonevertheless provide effective analgesia. In certain preferredembodiments of the method, the dose of opioid antagonist appreciablyaffects a surrogate measure of opioid analgesic effect. In certainpreferred embodiments, the amount of antagonist included in the oraldosage form is less positively reinforcing (e.g., less “liked”) by anon-physically dependent subject than a comparable oral dosage formwithout the antagonist included.

[0040] The oral pharmaceutical compositions containing the inventivecombination of drugs set forth herein may be in the form of tablets,liquids, troches, lozenges, aqueous or oily suspensions,multiparticulate formulations including dispersable powders, granules,matrix spheroids or coated inert beads, emulsions, hard or soft capsulesor syrups or elixirs, microparticles (e.g., microcapsules, microspheresand the like), buccal tablets, etc. The dosage forms of the presentinvention may include any desired pharmaceutically acceptable excipientsknown to those skilled in the art. The dosage forms may further providean immediate release of the opioid agonist and the opioid antagonist. Incertain preferred embodiments, the dosage forms provide a sustainedrelease of the opioid agonist, and provide the part or all of the doseof opioid antagonist in (i) immediate release form, (ii) sustainedrelease form, or (iii) both immediate and sustained release form. Suchembodiments may further comprise a portion of the opioid agonist inimmediate release form. Sustained release may be accomplished inaccordance with formulations/methods of manufacture known to thoseskilled in the art of pharmaceutical formulation, e.g., via theincorporation of a sustained release carrier into a matrix containingthe opioid agonist and opioid antagonist; or via a sustained releasecoating of a matrix containing the opioid agonist and opioid antagonist.

[0041] The invention may provide for a safer product (eg, lessrespiratory depression) as well as one with a slower rate of opioidtolerance and physical dependency development.

[0042] In certain other preferred embodiments, the opioid included inthe dosage form is a different orally active opioid agonist thanhydrocodone. The ratio of naltrexone included in such formulations canbe readily determined based on a simple calculation, taking into accountthe known equianalgesic dosages of various opioid analgesics as comparedto hydrocodone. Equianalgesic dosages of various opioid analgesics areprovided below, and are otherwise known to those skilled in the art,e.g, from Foley, K. “The Treatment of Cancer Pain;” N. Engl. J. Med.1985;313:84-95, hereby incorporated by reference. In yet further aspectsof this embodiment, a different opioid antagonist is substituted fornaltrexone, using equiantagonistic doses thereof.

[0043] In certain embodiments, a combination of two opioid analgesics isincluded in the formulation. In further embodiments, one or more opioidanalgesics is included and a further non-opioid drug is also included,in addition to the opioid antagonist. Such non-opioid drugs wouldpreferably provide additional analgesia, and,include, for example,aspirin, acetaminophen, non-steroidal antiinflammatory drugs (“NSAIDS”),NMDA antagonists, and cycooxygenase-II inhibitors (“COX-II inhibitors”).In yet further embodiments, a non-opioid drug can be included whichprovides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, or antihistamine drugs, and the like.

[0044] The term “parenterally” as used herein includes subcutaneousinjections, intravenous, intramuscular, intrastemal injection orinfusion techniques.

[0045] The term “effective analgesia” is defined for purposes of thepresent invention as a satisfactory reduction in or elimination of pain,along with a tolerable level of side effects, as determined by the humanpatient.

[0046] The term “sustained release” is defined for purposes of thepresent invention as the release of the drug (opioid analgesic) from theoral formulation at such a rate that blood (e.g., plasma) concentrations(levels) are maintained within the therapeutic range (above the minimumeffective analgesic concentration or “WEAC”) but below toxic levels overa period of time indicative of a twice-a-day or a once-a-dayformulation.

[0047] The term “steady state” refers to a time when the rate ofelimination of a drug is the same as the rate of absorption of that druginto the body.

[0048] For purposes of the present invention, the term “opioid agonist”is interchangeable with the term “opioid” or “opioid analgesic” andshall include the base of the opioid, mixed agonist-antagonists, partialagonists, pharmaceutically acceptable salts thereof, stereoisomersthereof, ethers and esters thereof, and mixtures thereof.

[0049] For purposes of the present invention, the term “opioidantagonist” shall include the base, pharmaceutically acceptable saltsthereof, stereoisomers thereof, ethers and esters thereof, and mixturesthereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0050] The following drawings are illustrative of embodiments of theinvention and are not meant to limit the scope of the invention asencompassed by the claims.

[0051]FIG. 1 shows the naltrexone antagonism of hydrocodone-induced VAS(Visual Analog Scale) “drug effect” for Example 1;

[0052]FIG. 2 presents the naltrexone antagonism of hydrocodone-inducedpupillary constriction for Example 1;

[0053]FIG. 3 presents the mean “drag effect” VAS score over time foreach of the treatments of Example 2;

[0054]FIG. 4 presents the mean “drug effect” pupil diameters over timefor each of the treatments of Example 2;

[0055]FIGS. 5 and 6 present the corresponding mean maximum “drug effect”VAS score (±95% CI) and mean minimum pupil diameter (±95% CI) versus thelog from each of the naltrexone doses of Example 2;

[0056]FIG. 7A illustrates the subjects'ability to feel the effect ofhydrocodone in the presence of varying amounts of naltrexone in Example3;

[0057]FIGS. 7B and 7C illustrate the subjects'favorable or unfavorablesubjective experiences of hydrocodone in the presence of varying amountsof naltrexone, respectively, for Example 3;

[0058]FIG. 8A illustrates the subjects'perception of withdrawal from theeffect of hydrocodone in the presence of varying amounts of naltrexonein Example 3;

[0059]FIG. 8B illustrates the subjective experience of illness in thepresence of varying amounts of naltrexone in Example 3;

[0060]FIG. 9A illustrates the effect on pupil size of hydrocodone in thepresence of varying amounts of naltrexone in Example 3;

[0061]FIG. 9B illustrates the apparent extent of withdrawal from theeffect of hydrocodone in the presence of varying amounts of naltrexonein Example 3, from the perspective of the observer;

[0062] FIGS. 10A-C present the areas under the curves presented in FIGS.7A-C, integrated over the 6 hour observation period, as a function ofnaltrexone dose, and the 95% confidence levels for the placebo responseof naltrexone (30 mg hydrocodone, 0 mg naltrexone); and

[0063] FIGS. 11A-C present the areas under the curves presented in FIG.8A-B and FIG. 9A, integrated over the 6 hour observation period, as afunction of naltrexone dose, and the 95% confidence levels for theplacebo response of naltrexone (30 mg hydrocodone, 0 mg naltrexone).

DETAILED DESCRIPTION OF THE INVENTION

[0064] It has been postulated that there exists at least threesubspecies of opioid receptors, designated mu, kappa, and delta. Withinthis framework, the mu receptor is considered to be involved in theproduction of superspinal analgesia, respiratory depression, euphoria,and physical dependence. The kappa receptor is considered to be involvedin inducing spinal analgesia, miosis and sedation. Activation of thegamma receptors causes dysphoria and hallucinations, as well asrespiratory and vasomotor stimulatory effects. A receptor distinct fromthe mu receptor and designated gamma has been described in the mouse vasdeferens, Lord, et al. Nature, 1977, 267, 495-99. Opioid agonists arethought to exert their agonist actions primarily at the mu receptor andto a lesser degree at the kappa receptor. There are a few drugs thatappear to act as partial agonists at one receptor type or another. Suchdrugs exhibit a ceiling effect. Such drugs include nalorphine, propiram,and buprenorphine. Still other drugs act as competitive antagonists atthe mu receptor and block the effects of morphine-like drugs, byexerting agonist actions at the kappa and omega receptors. The term“agonist-antagonist” has evolved to describe such mechanism of actions.The concept of antagonism to the actions of opioids is considered to becomplex.

[0065] It has been found with the administration of opioidagonist-antagonists and partial agonists that tolerance develops to theagonist effects but not to the antagonist effects of the drugs. Evenafter prolonged administration of high doses, discontinuance of naloxoneis not characterized by any recognizable withdrawal syndrome, andwithdrawal of naltrexone, another relatively pure opioid antagonist,produces very few signs and symptoms. However, after prolongedadministration of high dosage, abrupt discontinuation of opioidagonist-antagonists nalorphine or cyclazocine causes a characteristicwithdrawal syndrome that is similar for both drugs.

[0066] Naloxone is an opioid antagonist which is almost void of agonisteffects. Subcutaneous doses of up to 12 mg of naloxone produce nodiscernable subjective effects, and 24 mg naloxone causes only slightdrowsiness. Small doses (0.4-0.8 mg) of naloxone given intramuscularlyor intravenously in man prevent or promptly reverse the effects ofmorphine-like opioid agonist. One mg of naloxone intravenously has beenreported to completely block the effect of 25 mg of heroin. The effectsof naloxone are seen almost immediately after intravenousadministration. The drug is absorbed after oral administration, but hasbeen reported to be metabolized into an inactive form rapidly in itsfirst passage through the liver such that it has been reported to beonly one fiftieth as potent as when parenterally administered. Oraldosage of more than 1 g have been reported to be almost completelymetabolized in less than 24 hours.

[0067] Other opioid antagonists, for example, cyclazocine andnaltrexone, both of which have cyclopropylmethyl substitutions on thenitrogen, retain much of their efficacy by the oral route and theirdurations of action are much longer, approaching 24 hours after oraldoses. A most preferred opioid antagonist is naltrexone. However,equiantagonistic oral doses of other opioid antagonists, including butnot limited to naloxone, nalmephene, cyclazocine, and levallorphan canbe utilized in accordance with the present invention. The ratio of suchother antagonists to a particular opioid agonist can be readilydetermined without undue experimentation by one skilled in art whodesires to utilize a different opioid antagonist than naltrexone, theratio of which to opioid agonists is exemplified and discussed in detailherein. Those skilled in the art may determine such ratios of otherantagonists to opioid agonists, e.g., by conducting the same or similarclinical studies set forth in the examples appended herein. Thus,combinations of opioid antagonists/opioid agonists which are orallyadministered in ratios which are equivalent to the ratio of, e.g.,naltrexone to hydrocodone set forth herein are considered to be withinthe scope of the present invention and within the scope of the appendedclaims. For example, in certain embodiments of the invention, naloxoneis utilized as the opioid antagonist, the amount of naloxone included inthe dosage form being large enough to provide an equiantagonistic effectas if naltrexone were included in the combination.

[0068] In the treatment of patients previously addicted to opioids,naltrexone has been used in large oral doses (over 100 mg) to preventeuphorigenic effects of opioid agonists. Naltrexone has been reported toexert strong preferential blocking action against mu over delta sites.Naltrexone is known as a synthetic congener of oxymorphone with noopioid agonist properties, and differs in structure from oxymorphone bythe replacement of the methyl group located on the nitrogen atom ofoxymorphone with a cyclopropylmethyl group. The hydrochloride salt ofnaltrexone is soluble in water up to about 100mg/cc. The pharmacologicaland pharmacokinetic properties of naltrexone have been evaluated inmultiple animal and clinical studies. See, e.g., Gonzalez J P, et al.Naltrexone: A review of its Pharmacodynamic and PharmacokineticProperties and Therapeutic Efficacy in the Management of OpioidDependence. Drugs 1988; 35:192-213, hereby incorporated by reference.Following oral administration, naltrexone is rapidly absorbed (within 1hour) and has an oral bioavailability ranging from 5-40%. Naltrexone'sprotein binding is approximately 21% and the volume of distributionfollowing single-dose administration is 16.1 L/kg.

[0069] Naltrexone is commercially available in tablet form (Revia®,DuPont) for the treatment of alcohol dependence and for the blockade ofexogenously administered opioids. A, e.g., Revia (naltrexonehydrochloride tablets). Physician's Desk Reference 51^(st) ed.,Montvale, N.J. “Medical Economics” 1997;51:957-959. A dosage of 50mgReVia® blocks the pharmacological effects of 25mg IV administered heroinfor up to 24 hours.

[0070] It is known that when coadministered with morphine, heroin orother opioids on a chronic basis, naltrexone blocks the development ofphysical dependence to opioids. It-is believed that the method by whichnaltrexone blocks the effects of heroin is by competitively binding atthe opioid receptors. Naltrexone has been used to treat narcoticaddiction by complete blockade of the effects of opioids. It has beenfound that the most successful use of naltrexone for a narcoticaddiction is with good prognosis narcotic addicts as part of acomprehensive occupational or rehabilitative program involvingbehavioral control or other compliance enhancing methods. For treatmentof narcotic dependence with naltrexone, it is desirable that the patientbe opioid-free for at least 7-10 days. The initial dosage of naltrexonefor such purposes has typically been about 25 mg, and if no withdrawalsigns occur, the dosage may be increased to 50 mg per day. A dailydosage of 50 mg is considered to produce adequate clinical blockade ofthe actions of parenterally administered opioids. Naltrexone has alsobeen used for the treatment of alcoholism as an adjunct with social andpsychotherapeutic methods.

[0071] In the dosage forms and methods of the invention, the amount ofnaltrexone included is significantly less than the dosages previouslycommercially available. This is in part because the use of naltrexone isdifferent in the present invention: the goal is not to block opioideffects, but rather to provide a negative, “aversive” experience when alarge amount of the combination product, e.g., about 2-3 times theusually prescribed dose, is taken by or administered to a physicallydependent subject.

[0072] Thus, for example, in formulations of the present invention inwhich the opioid is hydrocodone bitartrate 15 mg, the amount ofnaltrexone hydrochloride included in the formulation is from about 0.5mg to about 4 mg, and preferably from about 0.75 mg to about 3 mgnaltrexone per 15 mg hydrocodone.

[0073] Opioid analgesics which are useful in the present inventioninclude all opioid agonists or mixed agonist-antagonists, partialagonists, including but not limited to alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diampromide, diarnorphone, dihydrocodeine, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, metopon, morphine, myrophine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene,normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, piritramide, propheptazine, promedol, properidine,pro-poxyphene, sufentanil, tilidine, tramadol, mixtures of any of theforegoing, salts of any of the foregoing, and the like.

[0074] In certain preferred embodiments, the opioid agonist or analgesicis selected from the group consisting of hydrocodone, morphine,hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone,or salts thereof, or mixtures thereof. In certain preferred embodiments,the opioid agonist is hydrocodone. Equianalgesic doses of these opioids,in comparision to a 15 mg dose of hydrocodone, are set forth in Table 1below: TABLE 1 Equianalgesic Doses of Opiolds Oploid Calculated Dose(mg) Oxycodone 13.5 Codeine 90.0 Hydrocodone 15.0 Hydromorphone 3.375Levorphanol 1.8 Meperidine 135.0 Methadone 9.0 Morphine 27.0

[0075] Based on the preferred ratio of naltrexone in an amount fromabout 0.5 to about 4 mg per 15 mg of hydrocodone, the approximate ratioof naltrexone to 1mg of each opioid is set forth in Table 2: TABLE 2Weight Ratio of Naltrexone per Dose Opioid Weight Ratio Naltrexone perOpioid 1 mg Opioid Oxycodone 0.037 to 0.296 Codeine 0.005 to 0.044Hydrocodone 0.033 to 0.267 Hydromorphone 0.148 to 1.185 Levorphanol0.278 to 2.222 Meperidine 0.0037 to 0.0296 Methadone 0.056 to 0.444Morphine 0.018 to 0.148

[0076] Based on the more preferred ratio of about 0.75 mg to about 3 mgnaltrexone per 15 mg hydrocodone of naltrexone, the approximate ratio ofnaltrexone to 1 mg of each opioid is set forth in Table 3: TABLE 3Weight Ratio of Naltrexone per Dose Opioid Opioid Weight RatioNaltrexone Oxycodone 0.056 to 0.222 Codeine 0.0083 to 0.033 Hydrocodone0.050 to 0.200 Hydromorphone 0.222 to 0.889 Levorphanol 0.417 to 1.667Meperidine 0.0056 to 0.022 Methadone 0.083 to 0.333 Morphine 0.028 to0.111

[0077] Although hydrocodone is effective in the management of pain,there has been an increase in its abuse by individuals who arepsychologically dependent on opioids or who misuse opioids fornon-therapeutic reasons. Previous experience with other opioids hasdemonstrated a decreased abuse potential when opioids are administeredin combination with a narcotic antagonist especially in patients who areex-addicts. Weinhold L L, et al. Buprenorphine Alone and in Combinationwith Naltrexone in Non-Dependent Humans, Drug and Alcohol Dependence1992; 30:263-274; Mendelson J., et. al., Buprenorphine and NaloxoneInteractions in Opiate-Dependent Volunteers, Clin Pharm Ther 1996;60:105-114; both of which are hereby incorporated by reference.

[0078] Hydrocodone is a semisynthetic narcotic analgesic and antitussivewith multiple central nervous system and gastrointestinal actions.Chemically, hydrocodone is 4,5-epoxy-3-methoxy-17-methylmorphinan-6-one,and is also known as dihydrocodeinone. Like other opioids, hydrocodonemay be habit forming and may produce drug dependence of the morphinetype. In excess doses hydrocodone, like other opium derivatives, willdepress respiration.

[0079] Oral hydrocodone is also available in Europe (Belgium, Germany,Greece, Italy, Luxembourg, Norway and Switzerland) as an antitussiveagent. A parenteral formulation is also available in Germany as anantitussive agent. For use as an analgesic, hydrocodone bitartrate iscommercially available in the United States only as a fixed combinationwith non-opiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.)for relief of moderate or moderately severe pain.

[0080] A common dosage form of hydrocodone is in combination withacetaminophen, and is commercially available, e.g., as Lortab®in theU.S. from UCB Pharma, Inc. as 2.5/500 mg, 5/500 mg, 7.5/500 mg and10/500 mg hydrocodone/acetaminophen tablets. Tablets are also availablein the ratio of 7.5 mg hydrocodone bitartrate and 650 mg acetaminophen;and 7.5 mg hydrocodone bitartrate and 750 mg acetaminophen. Hydrocodonein combination with aspirin is given in an oral dosage form to adultsgenerally in 1-2 tablets every 4-6 hours as needed to alleviate pain.The tablet form is 5mg hydrocodone bitartrate and 224 mg aspirin with 32mg caffeine; or 5 mg hydrocodone bitartrate and 500 mg aspirin. Arelatively new formulation comprises hydrocodone bitartrate andibuprofen. Vicoprofen®, commercially available in the U.S. from KnollLaboratories, is a tablet containing 7.5 mg hydrocodone bitartrate and200 mg ibuprofen. The present invention is contemplated to encompass allsuch formulations, with the inclusion of the orally active opioidantagonist within the inventive amounts set forth herein.

[0081] The abuse potential of opioid analgesics such as hydrocodone issurprisingly curtailed by the inventive combinations of the presentinvention. More particularly, it has been discovered that it is possibleto combine in a single oral dosage form an opioid analgesic togetherwith a small amount of opioid antagonist, to achieve a product whichstill provides analgesia but which substantially negates the possibilitythat a physically dependent human subject will continue to abuse thedrug by taking more than one tablet at a time, e.g., 2-3 times more thanthe usually prescribed dose.

[0082] The oral dosage forms of the invention comprise an orallytherapeutically effective amount of an opioid agonist, together with anopioid antagonist such as naltrexone in an amount (i) which does notcause a reduction in the level of analgesia elicited from the dosageform upon oral administration to a non-therapeutic level and (ii) whichprovides at least a mildly negative, “aversive” experience in physicallydependent human subjects, for example, physically dependent addicts(e.g., precipitated abstinence syndrome) when taking more than theusually prescribed dose at a time. Preferably, the amount of antagonistincluded in the oral dosage form is (iii) less positively reinforcing(e.g., less “liked” ) by a non-physically dependent human subject, e.g.,opioid addict, than a comparable oral dosage form without the antagonistincluded.

[0083] The amount of antagonist which is useful to achieve parameters(i)-(iii) set forth in the preceding paragraph may be determined atleast in part, for example, through the use of “surrogate” tests, suchas a VAS scale (where the subject grades his/her perception of theeffect of the dosage form) and/or via a measurement such as pupil size(measured by pupillometry). Such measurements allow one skilled in theart to determine the dose of antagonist relative to the dose of agonistwhich causes a diminution in the opiate effects of the agonist.Subsequently, one skilled in the art can determine the level of opioidantagonist that causes aversive effects in physically dependent subjectsas well as the level of opioid antagonist that minimizes “liking scores”or opioid reinforcing properties in non-physically dependent addicts.Once these levels of opioid antagonist are determined, it is thenpossible to determine the range of antagonist dosages at or below thislevel which would be useful in achieving parameters (i)-(iii) set forthin the preceding paragraph.

[0084] The combination of opioid agonist and opioid antagonist can beemployed in admixtures with conventional excipients, i.e.,pharmaceutically acceptable organic or inorganic carrier substancessuitable for oral administration, known to the art. Suitablepharmaceutically acceptable carriers include but are not limited towater, salt solutions, alcohols, gum arabic, vegetable oils, benzylalcohols, polyethylene glycols, gelate, carbohydrates such as lactose,amylose or starch, magnesium stearate talc, silicic acid, viscousparaffin, perfume oil, fatty acid monoglycerides and diglycerides,pentaerythritol fatty acid esters, hydroxymethylcellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure buffers, coloring, flavoring and/oraromatic substances and the like. They can also be combined wheredesired with other active agents, e.g., other analgesic agents. For oraladministration, particularly suitable are tablets, dragees, liquids,drops, suppositories, or capsules, caplets and gelcaps. The compositonsintended for oral use may be prepared according to any method known inthe art and such compositions may contain one or more agents selectedfrom the group consisting of inert, non-toxic pharmaceuticallyexcipients which are suitable for the manufacture of tablets. Suchexcipients include, for example an inert diluent such as lactose;granulating and disintegrating agents such as cornstarch; binding agentssuch as starch; and lubricating agents such as magnesium stearate. Thetablets may be uncoated or they may be coated by known techniques forelegance or to delay release of the active ingredients. Formulations fororal use may also be presented as hard gelatin capsules wherein theactive ingredient is mixed with an inert diluent.

[0085] Aqueous suspensions contain the above-identified combination ofdrugs and that mixture has one or more excipients suitable as suspendingagents, for example pharmaceutically acceptable synthetic gums such ashydroxypropylmethylcellulose or natural gums. Oily suspensions may beformulated by suspending the above-identified combination of drugs in avegetable oil or mineral oil. The oily suspensions may contain athickening agent such as beeswax or cetyl alcohol. A syrup, elixir, orthe like can be used wherein a sweetened vehicle is employed. Injectablesuspensions may also be prepared, in which case appropriate liquidcarriers, suspending agents and the like may be employed.

[0086] The method of treatment and pharmaceutical formulations of thepresent invention may further include one or more drugs in addition tothe opioid analgesic and opioid antagonist, which additional drug(s) mayor may not act synergistically therewith. Thus, in certain embodiments,a combination of two opioid analgesics may be included in theformulation, in addition to the opioid antagonist. For example, the,dosage form may include two opioid analgesics having differentproperties, such as half-life, solubility, potency, and a combination ofany of the foregoing. In yet further embodiments, one or more opioidanalgesics is included and a further non-opioid drug is also included,in addition to the opioid antagonist. Such non-opioid drugs wouldpreferably provide additional analgesia, and include, for example,aspirin; acetaminophen; non-sterioidal antiinflammatory drugs(“NSAIDS”), e.g., ibuprofen, ketoprofen, etc.; N-methyl-D-aspartate(NMDA) receptor antagonists, e.g., a morphinan such as dextromethorphanor dextrorphan, or ketamine; cycooxygenase-II inhibitors (“COX-IIinhibitors”); and/or glycine receptor antagonists.

[0087] In certain preferred embodiments of the present invention, theinvention allows for the use of lower doses of the opioid analgesic byvirtue of the inclusion of an additional non-opioid agonist, such as anNSAID or a COX-2 inhibitor. By using lower amounts of either or bothdrugs, the side effects associated with effective pain management inhumans are reduced.

[0088] Suitable non-steroidal anti-inflammatory agents, includingibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen,flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin,pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zido-metacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam or isoxicam, and the like. Useful dosages of these drugs arewell known to those skilled in the art.

[0089] N-methyl-D-aspartate (NMDA) receptor antagonists are well knownin the art, and encompass, for example, morphinans such asdextromethorphan or dextrorphan, ketamine, d-methadone orpharmaceutically acceptable salts thereof. For purposes of the presentinvention, the term “NMDA antagonist” is also deemed to encompass drugsthat block a major intracellular consequence of NMDA-receptoractivation, e.g. a ganglioside such as GM₁ or GT_(1b)a phenothiazinesuch as trifluoperazine or a naphthalenesulfonamide such asN-(6-aminothexyl)-5-chloro-1-naphthalenesulfonamide. These drugs arestated to inhibit the development of tolerance to and/or dependence onaddictive drugs, e.g., narcotic analgesics such as morphine, codeine,etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et.al.),and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et. al.),all of which are hereby incorporated by reference. The NMDA antagonistmay be included alone, or in combination with a local anesthetic such aslidocaine, as described in these Mayer, et.al. patents.

[0090] The treatment of chronic pain via the use of glycine receptorantagonists and the identification of such drugs is described in U.S.Pat. No. 5,514,680 (Weber, et al.), hereby incorporated by reference.

[0091] COX-2 inhibitors have been reported in the art and many chemicalstructures are known to produce inhibition of cyclooxygenase-2. COX-2inhibitors are described, for example, in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995;5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and5,130,311, all of which are hereby incorporated by reference. Certainpreferred COX-2 inhibitors include celecoxib (SC-58635), DUP-697,flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid(6-MNA), MK-966, nabumetone (prodrug for 6-MNA), nimesulide, NS-398,SC-5766, SC-58215, T-614; or combinations thereof Dosage levels of COX-2inhibitor on the order of from about 0.005 mg to about 140 mg perkilogram of body weight per day are therapeutically effective incombination with an opioid analgesic. Alternatively, about 0.25 mg toabout 7 g per patient per day of a COX-2 inhibitor is administered incombination with an opioid analgesic.

[0092] In yet further embodiments, a non-opioid drug can be includedwhich provides a desired effect other than analgesia, e.g., antitussive,expectorant, decongestant, antihistamine drugs, local anesthetics, andthe like.

[0093] An oral dosage form according to the invention may be providedas, for example, granules, spheroids, beads, pellets (hereinaftercollectively referred to as “multiparticulates”). An amount of themultiparticulates which is effective to provide the desired dose ofopioid over time may be placed in a capsule or may be incorporated inany other suitable oral solid form. Alternatively, the oral dosage formmay be in the form of a tablet.

Controlled Release Dosage Forms

[0094] The opioid agonist/opioid antagonist combination can beformulated as a controlled or sustained release oral formulation in anysuitable tablet, coated tablet or multiparticulate formulation known tothose skilled in the art. The sustained release dosage form mayoptionally include a sustained release carrier which is incorporatedinto a matrix along with the opioid agonist and opioid antagonist, ormay be applied as a sustained release coating.

[0095] In embodiments in which the opioid analgesic compriseshydrocodone, the sustained release oral dosage forms may includeanalgesic doses from about 8 mg to about 50 mg of hydrocodone per dosageunit. In sustained release oral dosage forms where hydromorphone is thetherapeutically active opioid, it is included in an amount from about 2mg to about 64 mg hydromorphone hydrochloride. In another embodiment,the opioid analgesic comprises morphine, and the sustained release oraldosage forms of the present invention include from about 2.5 mg to about800 mg morphine, by weight. In yet another embodiment, the opioidanalgesic comprises oxycodone and the sustained release oral dosageforms include from about 2.5 mg to about 800 mg oxycodone. The opioidanalgesic may comprise tramadol and the sustained release oral dosageforms may include from about 25 mg to 800 mg tramadol per dosage unit.The dosage form may contain more than one opioid analgesic to provide asubstantially equivalent therapeutic effect. Alternatively, the dosageform may contain molar equivalent amounts of other salts of the opioidsuseful in the present invention.

[0096] In one preferred embodiment of the present invention, thesustained release dosage form comprises such particles containing orcomprising the active ingredient, wherein the particles have diameterfrom about 0. 1 mm to about 2.5 mm, preferably from about 0.5 mm toabout 2 mm.

[0097] The particles are preferably film coated with a material thatpermits release of the opioid agonist/antagonist combination at asustained rate in an aqueous medium. The film coat is chosen so as toachieve, in combination with the other stated properties, a desiredin-vitro release rate. The sustained release coating formulations of thepresent invention should be capable of producing a strong, continuousfilm that is smooth and elegant, capable of supporting pigments andother coating additives, non-toxic, inert, and tack-free.

[0098] In certain embodiments, the particles comprise normal releasematrixes containing the opioid analgesic with the opioid antagonist.

Coatings

[0099] The dosage forms of the present invention may optionally becoated with one or more materials suitable for the regulation of releaseor for the protection of the formulation. In one embodiment, coatingsare provided to permit either pH-dependent or pH-independent release,e.g., when exposed to gastrointestinal fluid. A pH-dependent coatingserves to release the opioid in desired areas of the gastro-intestinal(GI) tract, e.g., the stomach or small intestine, such that anabsorption profile is provided which is capable of providing at leastabout eight hours and preferably about twelve hours to up to abouttwenty-four hours of analgesia to a patient. When a pH-independentcoating is desired, the coating is designed to achieve optimal releaseregardless of pH-changes in the environmental fluid, e.g., the GI tract.It is also possible to formulate compositions which release a portion ofthe dose in one desired area of the GI tract, e.g., the stomach, andrelease the remainder of the dose in another area of the GI tract, e.g.,the small intestine.

[0100] Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug is coated over the enteric coat and is releasedin the stomach, while the remainder, being protected by the entericcoating, is released further down the gastrointestinal tract. Coatingswhich are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate PVAP), hydroxypropylmethylcellulose phthalate, andmethacrylic acid ester copolymers, zein, and the like.

[0101] In certain preferred embodiments, the substrate (e.g., tabletcore bead, matrix particle) containing the opioid analgesic (with orwithout the COX-2 inhibitor) is coated with a hydrophobic materialselected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii)mixtures thereof. The coating may be applied in the form of an organicor aqueous solution or dispersion. The coating may be applied to obtaina weight gain from about 2 to about 25% of the substrate in order toobtain a desired sustained release profile. Coatings derived fromaqueous dispersions—are described, e.g., in detail in U.S. Pat. Nos.5,273,760 and 5,286,493, assigned to the Assignee of the presentinvention and hereby incorporated by reference.

[0102] Other examples of sustained release formulations and coatingswhich may be used in accordance with the present invention includeAssignee's U.S. Pat. Nos. 5,324,351; 5,356,467, and 5,472,712, herebyincorporated by reference in their entirety.

[0103] Alkycellulose Polymers

[0104] Cellulosic materials and polymers, including alkylcelluloses,provide hydrophobic materials well suited for coating the beadsaccording to the invention. Simply by way of example, one preferredalkylcellulosic polymer is ethylcellulose, although the artisan willappreciate that other cellulose and/or alkylcellulose polymers may bereadily employed, singly or in any combination, as all or part of ahydrophobic coating according to the invention.

[0105] One commercially-available aqueous dispersion of ethylcelluloseis Aquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® isprepared by dissolving the ethylcellulose in a water-immiscible organicsolvent and then emulsifying the same in water in the presence of asurfactant and a stabilizer. After homogenization to generate submicrondroplets, the organic solvent is evaporated under vacuum to form apseudolatex. The plasticizer is not incorporated in the pseudolatexduring the manufacturing phase. Thus, prior to using the same as acoating, it is necessary to intimately mix the Aquacoat® with a suitableplasticizer prior to use.

[0106] Another aqueous dispersion of ethylcellulose is commerciallyavailable as Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). Thisproduct is prepared by incorporating plasticizer into the dispersionduring the manufacturing process. A hot melt of a polymer, plasticizer(dibutyl sebacate), and stabilizer (oleic acid) is prepared as ahomogeneous mixture, which is then diluted with an alkaline solution toobtain an aqueous dispersion which can be applied directly ontosubstrates.

[0107] Acrylic Polymers

[0108] In other preferred embodiments of the present invention, thehydrophobic material comprising the controlled release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate,poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), polymethacrylate, poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), and glycidyl methacrylateco-polymers.

[0109] In certain preferred embodiments, the acrylic polymer iscomprised of one or more ammonio methacrylate copolymers. Ammoniomethacrylate copolymers are well known in the art, and are described inNF XVII as fully polymerized copolymers of acrylic and methacrylic acidesters with a low content of quaternary ammonium groups.

[0110] In order to obtain a desirable dissolution profile, it may benecessary to incorporate two or more ammonio methacrylate copolymershaving differing physical properties, such as different molar ratios ofthe quaternary ammonium groups to the neutral (meth)acrylic esters.

[0111] Certain methacrylic acid ester-type polymers are useful forpreparing pH-dependent coatings which may be used in accordance with thepresent invention. For example, there are a family of copolymerssynthesized from diethylaminoethyl methacrylate and other neutralmethacrylic esters, also known as methacrylic acid copolymer orpolymeric methacrylates, commercially available as Eudragite from RohmTech, Inc. There are several different types of Eudragit®. For example,Eudragit® E is an example of a methacrylic acid copolymer which swellsand dissolves in acidic media. Eudragit® L is a methacrylic acidcopolymer which does not swell at about pH<5.7 and is soluble at aboutpH>6. Eudragit® S does not swell at about pH<6.5 and is soluble at aboutpH>7. Eudragit® RL and Eudragit® RS are water swellable, and the amountof water absorbed by these polymers is pH-dependent, however, dosageforms coated with Eudragit®RL and RS are pH-independent.

[0112] In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragie® RL30D and Eudragit® RS30D,respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit®RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

[0113] The Eudragit® RL/RS dispersions of the present invention may bemixed together in any desired ratio in order to ultimately obtain asustained release formulation having a desirable dis-solution profile.Desirable sustained release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L.

[0114] Plasticizers

[0115] In embodiments of the present invention where the coatingcomprises an aqueous dispersion of a hydrophobic material, the inclusionof an effective amount of a plasticizer in the aqueous dispersion ofhydrophobic material will further improve the physical properties of thesustained release coating. For example, because ethylcellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it is preferable to incorporate aplasticizer into an ethylcellulose coating containing sustained releasecoating before using the same as a coating material. Generally, theamount of plasticizer included in a coating solution is based on theconcentration of the film-former, e.g., most often from about 1 to about50 percent by weight of the film-former. Concentration of theplasticizer, 30 however, can only be properly determined after carefulexperimentation with the particular coating solution and method ofapplication.

[0116] Examples of suitable plasticizers for ethylcellulose includewater insoluble plasticizers such as dibutyl sebacate, diethylphthalate, triethyl citrate, tributyl citrate, and triacetin, althoughit is possible that other water-insoluble plasticizers (such asacetylated monoglycerides, phthalate esters, castor oil, etc.) may beused. Triethyl citrate is an especially preferred plasticizer for theaqueous dispersions of ethyl cellulose of the present invention.

[0117] Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

[0118] It has further been found that the addition of a small amount oftalc reduces the tendency of the aqueous dispersion to stick duringprocessing, and acts as a polishing agent.

Processes for Preparing Coated Beads

[0119] When a hydrophobic material is used to coat inert pharmaceuticalbeads such as nu pariel 18/20 beads, a plurality of the resultant solidcontrolled release beads may thereafter be placed in a gelatin capsulein an amount sufficient to provide an effective controlled release dosewhen ingested and contacted by an environmental fluid, e.g., gastricfluid or dissolution media.

[0120] The controlled release bead formulations of the present inventionslowly release the therapeutically active agent, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. The controlledrelease profile of the formulations of the invention can be altered, forexample, by varying the amount of overcoating with the hydrophobicmaterial, altering the manner in which the plasticizer is added to thehydrophobic material, by varying the amount of plasticizer relative tohydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc. The dissolutionprofile of the ultimate product may also be modified, for example, byincreasing or decreasing the thickness of the retardant coating.

[0121] Spheroids or beads coated with a therapeutically active agent areprepared, e.g., by dissolving the therapeutically active agent in waterand then spraying the solution onto a substrate, for example, nu pariel18/20 beads, using a Wuster insert. Optionally, additional ingredientsare also added prior to coating the beads in order to assist the bindingof the opioid to the beads, and/or to color the solution, etc. Forexample, a product which includes hydroxypropylmethylcellulose, etc.with or without colorant (e.g., Opadry®, commercially available fromColorcon, Inc.) may be added to the solution and the solution mixed(e.g., for about 1 hour) prior to application of the same onto thebeads. The resultant coated substrate, in this example beads, may thenbe optionally overcoated with a barrier agent, to separate thetherapeutically active agent from the hydrophobic controlled releasecoating. An example of a suitable barrier agent is one which compriseshydroxypropylmethylcellulose. However, any film-former known in the artmay be used. It is preferred that the barrier agent does not affect thedissolution rate of the final product.

[0122] The beads may then be overcoated with an aqueous dispersion ofthe hydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.triethyl citrate. Pre-formulated aqueous dispersions of ethyl-cellulose,such as Aquacoat® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

[0123] The coating solutions of the present invention preferablycontain, in addition to the film-former, plasticizer, and solvent system(i.e., water), a colorant to provide elegance and product distinction.Color may be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color may be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueousdispersion of an acrylic polymer is used include titanium dioxide andcolor pigments, such as iron oxide pigments. The incorporation ofpigments, may, however, increase the retard effect of the coating.

[0124] Plasticized hydrophobic material may be applied onto thesubstrate comprising the therapeutically active agent by spraying usingany suitable spray equipment known in the art. In a preferred method, aWurster fluidized-bed system is used in which an air jet, injected fromunderneath, fluidizes the core material and effects, drying while theacrylic polymer coating is sprayed on. A sufficient amount of thehydrophobic material to obtain a predetermined controlled release ofsaid therapeutically active agent when the coated substrate is exposedto aqueous solutions, e.g. gastric fluid, is preferably applied, takinginto account the physical characteristics of the therapeutically activeagent, the manner of incorporation of the plasticizer, etc. Aftercoating with the hydrophobic material, a further overcoat of afilm-former, such as Opadry®, is optionally applied to the beads. Thisovercoat is provided, if at all, in order to substantially reduceagglomeration of the beads.

[0125] The release of the therapeutically active agent from thecontrolled release formulation of the present invention can be furtherinfluenced, i.e., adjusted to a desired rate, by the addition of one ormore release-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic material to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

[0126] The release-modifying agents which function as pore-formers maybe organic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

[0127] The sustained release coatings of the present invention can alsoinclude erosion-promoting agents such as starch and gums.

[0128] The sustained release coatings of the present invention can alsoinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain.

[0129] The release-modifying agent may also comprise a semi-permeablepolymer.

[0130] In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

[0131] The sustained release coatings of the present invention may alsoinclude an exit means comprising at least one passageway, orifice, orthe like. The passageway may be formed by such methods as thosedisclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and4,088,864 (all of which are hereby incorporated by reference). Thepassageway can have any shape such as round, triangular, square,elliptical, irregular, etc.

Matrix Bead Formulations

[0132] In other embodiments of the present invention, the controlledrelease formulation is achieved via a matrix having a controlled releasecoating as set forth above. The present invention may also utilize acontrolled release matrix that affords in-vitro dissolution rates of theopioid within the preferred ranges and that releases the opioid in apH-dependent or pH-independent manner. The materials suitable forinclusion in a controlled release matrix will depend on the method usedto form the matrix.

[0133] For example, a matrix in addition to the opioid analgesic and(optionally) COX-2 may include:

[0134] Hydrophilic and/or hydrophobic materials, such as gums, celluloseethers, acrylic resins, protein derived materials; the list is not meantto be exclusive, and any pharmaceutically acceptable hydrophobicmaterial or hydrophilic material which is capable of impartingcontrolled release of the active agent and which melts (or softens tothe extent necessary to be extruded) may be used in accordance with thepresent invention.

[0135] Digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀), substitutedor unsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes,and stearyl alcohol; and polyalkylene glycols.

[0136] Of these polymers, acrylic polymers, especially Eudragit®RSPO—the cellulose ethers, especially hydroxyalkylcelluloses andcarboxyalkylcelluloses, are preferred. The oral dosage form may containbetween 1% and 80% (by weight) of at least one hydrophilic orhydrophobic material.

[0137] When the hydrophobic material is a hydrocarbon, the hydrocarbonpreferably has a melting point of between 25° and 90° C. Of the longchain hydrocarbon materials, fatty (aliphatic) alcohols are preferred.The oral dosage form may contain up to 60% (by weight) of at least onedigestible, long chain hydrocarbon.

[0138] Preferably, the oral dosage form contains up to 60% (by weight)of at least one polyalkylene glycol.

[0139] The hydrophobic material is preferably selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil, hydrogenatedvegetable oil, or mixtures thereof. In certain preferred embodiments ofthe present invention, the hydrophobic material is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid allylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial is selected from materials such as hydroxyalkylcelluloses suchas hydroxypropylmethylcellulose and mixtures of the foregoing.

[0140] Preferred hydrophobic materials are water-insoluble with more orless pronounced hydrophilic and/or hydrophobic trends. Preferably, thehydrophobic materials useful in the invention have a melting point fromabout 300 to about 200° C., preferably from about 45° to about 90° C.Specifically, the hydrophobic material may comprise natural or syntheticwaxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl orpreferably cetostearyl alcohol), fatty acids, including but not limitedto fatty acid esters, fatty acid glycerides (mono-, di-, andtri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearicaid, stearyl alcohol and hydrophobic and hydrophilic materials havinghydrocarbon backbones. Suitable waxes include, for example, beeswax,glycowax, castor wax and carnauba wax. For purposes of the presentinvention, a wax-like substance is defined as any material which isnormally solid at room temperature and has a melting point of from about30° to about 100° C.

[0141] Suitable hydrophobic materials which may be used in accordancewith the present invention include digestible, long chain (C₈-C₅₀ ,especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such asfatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils and natural and synthetic waxes. Hydrocarbons having amelting point of between 25° and 90° C. are preferred. Of the long chainhydrocarbon materials, fatty (aliphatic) alcohols are preferred incertain embodiments. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon.

[0142] Preferably, a combination of two or more hydrophobic materialsare included in the matrix formulations. If an additional hydrophobicmaterial is included, it is preferably selected from natural andsynthetic waxes, fatty acids, fatty alcohols, and mixtures of the same.Examples include beeswax, carnauba wax, stearic acid and stearylalcohol. This list is not meant to be exclusive.

[0143] One particular suitable matrix comprises at least one watersoluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy(C₁ to C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. Theamount of the at least one hydroxyalkyl cellulose in the present oraldosage form will be determined, inter alia, by the precise rate ofopioid release required. The at least one aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of the at least one aliphatic alcohol inthe present oral dosage form will be determined, as above, by theprecise rate of opioid release required. It will also depend on whetherat least one polyalkylene glycol is present in or absent from the oraldosage form. In the absence of at least one polyalkylene glycol, theoral dosage form preferably contains between 20% and 50% (by wt) of theat least one aliphatic alcohol. When at least one polyalkylehe glycol ispresent in the oral dosage form, then the combined weight of the atleast one aliphatic alcohol and the at least one polyalkylene glycolpreferably constitutes between 20% and 50% (by wt) of the total dosage.

[0144] In one embodiment, the ratio of, e.g., the at least onehydroxyalkyl cellulose or acrylic resin to the at least one aliphaticalcohol/ polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid from the formulation. A ratio of the at leastone hydroxyalkyl cellulose to the at least one aliphaticalcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with aratio of between 1:3 and 1:4 being particularly preferred.

[0145] The at least one polyalkylene glycol may be, for example,polypropylene glycol or, which is preferred, polyethylene glycol. Thenumber average molecular weight of the at least one poly-alkylene glycolis preferred between 1,000 and 15,000 especially between 1,500 and12,000.

[0146] Another suitable controlled release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

[0147] In another preferred embodiment, the matrix includes apharmaceutically acceptable combination of at least two hydrophobicmaterials.

[0148] In addition to the above ingredients, a controlled release matrixmay also contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

Processes for Preparing Matrix—Based Beads

[0149] In order to facilitate the preparation of a solid, controlledrelease, oral dosage form according to this invention, any method ofpreparing a matrix formulation known to those skilled in the art may beused. For example incorporation in the matrix may be effected, forexample, by (a) forming granules comprising at least one water solublehydroxyalkyl cellulose and opioid or an opioid salt; (b) mixing thehydroxyalkyl cellulose containing granules with at least one C₁₂ -C₃₆aliphatic alcohol; and (c) optionally, compressing and shaping thegranules. Preferably, the granules are formed by wet granulating thehydroxyalkyl cellulose/opioid with water. In a particularly preferredembodiment of this process, the amount of water added during the wetgranulation step is preferably between 1.5 and 5 times, especiallybetween 1.75 and 3.5 times, the dry weight of the opioid.

[0150] In yet other alternative embodiments, a spheronizing agent,together with the active ingredient can be spheronized to formspheroids. Microcrystalline cellulose is preferred. A suitablemicrocrystalline cellulose is, for example, the material sold as AvicelPH 101 (Trade Mark, FMC Corporation). In such-embodiments, in additionto the active ingredient and spheronizing agent, the spheroids may alsocontain a binder. Suitable binders, such as low viscosity, water solublepolymers, will be well known to those skilled in the pharmaceutical art.However, water soluble hydroxy lower alkyl cellulose, such ashydroxypropylcellulose, are preferred. Additionally (or alternatively)the spheroids may contain a water insoluble polymer, especially anacrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethylacrylate co-polymer, or ethyl cellulose. In such embodiments, thesustained release coating will generally include a hydrophobic materialsuch as (a) a wax, either alone or in admixture with a fatty alcohol; or(b) shellac or zein.

[0151] Melt Extrusion Matrix

[0152] Sustained release matrices can also be prepared viamelt-granulation or melt-extrusion techniques. Generally,melt-granulation techniques involve melting a normally solid hydrophobicmaterial, e.g. a wax, and incorporating a powdered drug therein. Toobtain a sustained release dosage form, it may be necessary toincorporate an additional hydrophobic substance, e.g. ethylcellulose ora water-insoluble acrylic polymer, into the molten wax hydrophobicmaterial. Examples of sustained release formulations prepared viamelt-granulation techniques are found in U.S. Pat. No. 4,861,598,assigned to the Assignee of the present invention and herebyincorporated by reference in its entirety.

[0153] The additional hydrophobic material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve constant release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like substances may be those with a water-solubilitythat is lower than about 1:5,000 (w/w).

[0154] In addition to the above ingredients, a sustained release matrixmay also contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation. In addition to the above ingredients,a sustained release matrix incorporating melt-extruded multiparticulatesmay also contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art in amounts upto about 50% by weight of the particulate if desired.

[0155] Specific examples of pharmaceutically acceptable carriers andexcipients that may be used to formulate oral dosage forms are describedin the Handbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein.

[0156] Melt Extrusion Multiparticulates

[0157] The preparation of a suitable melt-extruded matrix according tothe present invention may, for example, include the steps of blendingthe opioid analgesic, together with at least one hydrophobic materialand preferably the additional hydrophobic material to obtain ahomogeneous mixture. The homogeneous mixture is then heated to atemperature sufficient to at least soften the mixture sufficiently toextrude the same. The resulting homogeneous mixture is then extruded toform strands. The extrudate is preferably cooled and cut intomultiparticulates by any means known in the art. The strands are cooledand cut into multiparticulates. The multiparticulates are then dividedinto unit doses. The extrudate preferably has a diameter of from about0.1 to about 5 mm and provides sustained release of the therapeuticallyactive agent for a time period of from about 8 to about 24 hours.

[0158] An optional process for preparing the melt extrusions of thepresent invention includes directly metering into an extruder ahydrophobic material, a therapeutically active agent, and an optionalbinder; heating the homogenous mixture; extruding the homogenous mixtureto thereby form strands; cooling the strands containing the homogeneousmixture; cutting the strands into particles having a size from about 0.1mm to about 12 mm; and dividing said particles into unit doses. In thisaspect of the invention, a relatively continuous manufacturing procedureis realized.

[0159] The diameter of the extruder aperture or exit port can also beadjusted to vary the thickness of the extruded strands. Furthermore, theexit part of the extruder need not be round; it can be oblong,rectangular, etc. The exiting strands can be reduced to particles usinga hot wire cutter, guillotine, etc.

[0160] The melt extruded multiparticulate system can be, for example, inthe form of granules, spheroids or pellets depending upon the extruderexit orifice. For purposes of the present invention, the terms“melt-extruded multiparticulate(s)” and “melt-extruded multiparticulatesystem(s)” and “melt-extruded particles” shall refer to a plurality ofunits, preferably within a range of similar size and/or shape andcontaining one or more active agents and one or more excipients,preferably including a hydrophobic material as described herein. In thisregard, the melt-extruded multiparticulates will be of a range of fromabout 0.1 to about 12 mm in length and have a diameter of from about 0.1to about 5 mm. In addition, it is to be understood that themelt-extruded multiparticulates can be any geometrical shape within thissize range. Alternatively, the extrudate may simply be cut into desiredlengths and divided into unit doses of the therapeutically active agentwithout the need of a spheronization step.

[0161] In one preferred embodiment, oral dosage forms are prepared toinclude an effective amount of melt-extruded multiparticulates within acapsule. For example, a plurality of the melt-extruded multiparticulatesmay be placed in a gelatin capsule in an amount sufficient to provide aneffective sustained release dose when ingested and contacted by gastricfluid.

[0162] In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.

[0163] In yet another preferred embodiment, the extrudate can be shapedinto tablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et.al.), described in additional detail above and hereby incorporated byreference.

[0164] Optionally, the sustained release melt-extruded multiparticulatesystems or tablets can be coated, or the gelatin capsule can be furthercoated, with a sustained release coating such as the sustained releasecoatings described above. Such coatings preferably include a sufficientamount of hydrophobic material to obtain a weight gain level from about2 to about 30 percent, although the overcoat may be greater dependingupon the physical properties of the particular opioid analgesic compoundutilized and the desired release rate, among other things.

[0165] The melt-extruded unit dosage forms of the present invention mayfurther include combinations of melt-extruded multiparticulatescontaining one or more of the therapeutically active agents disclosedabove before being encapsulated. Furthermore, the unit dosage forms canalso include an amount of an immediate release therapeutically activeagent for prompt therapeutic effect. The immediate releasetherapeutically active agent may be incorporated, e.g., as separatepellets within a gelatin capsule, or may be coated on the surface of themultiparticulates after preparation of the dosage forms (e.g.,controlled release coating or matrix-based). The unit dosage forms ofthe present invention may also contain a combination of controlledrelease beads and matrix multiparticulates to achieve a desired effect.

[0166] The sustained release formulations of the present inventionpreferably slowly release the therapeutically active agent, e.g., wheningested and exposed to gastric fluids, and then to intestinal fluids.The sustained release profile of the melt-extruded formulations of theinvention can be altered, for example, by varying the amount ofretardant, i.e., hydrophobic material, by varying the amount ofplasticizer relative to hydrophobic material, by the inclusion ofadditional ingredients or excipients, by altering the method ofmanufacture, etc.

[0167] In other embodiments of the invention, the melt extruded materialis prepared without the inclusion of the therapeutically active agent,which is added thereafter to the extrudate. Such formulations typicallywill have the therapeutically active agent blended together with theextruded matrix material, and then the mixture would be tableted inorder to provide a slow release formulation. Such formulations may beadvantageous, for example, when the therapeutically active agentincluded in the formulation is sensitive to temperatures needed forsoftening the hydrophobic material and/ or the retardant material.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0168] The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

[0169] A direct comparison of the competitive antagonist properties ofnaltrexone following its coadministration with various opioid agonistshas not been undertaken previous to the present invention, to theknowledge of the inventors. However, dose-ranging studies have beenconducted evaluating the opioid antagonist properties in subjectsreceiving either heroin or morphine challenges. In general,preadministration of naltrexone 50 mg 24 hours prior to 25 mg ofintravenous heroin challenge completely blocked or attenuated the opioidagonist effects. See, Gonzalez J P, Broden R N. “Naltrexone: A Review ofits Pharmacodynamic and Pharmacokinetic Properties and TherapeuticEfficacy in the Management of Opioid Dependence.” Drugs 1988;35:192-213; Resnick R R, Valavka J, Freedman A M, Thomas M. “Studies ofEN-1639A (Naltrexone): A New Narcotic Antagonist.” Am. J. Psychiatry1974; 131:646-650, both of which are hereby incorporated by reference.

Example 1

[0170] In Example 1, a randomized, single-blind, placebo-controlled,single-dose, four-way crossover study was conducted which assessedwhether naltrexone oral solution 6.4 mg would block opioid agonistproperties of hydrocodone 15 mg in 6 normal, healthy, female volunteers.The study population included only females because previous observationshave indicated that females have an increased sensitivity to the opioidagonist effects as compared to males. The four treatments were HYIR/APAP(2 tablets of hydrocodone 7.5 and acetaminophen 750 mg, Vicodin ES®) andnaltrexone oral solution 3.2 mg, HYIR/APAP (2×7.5 mg) and naltrexoneoral solution 6.4 mg, HYIR comparator tablets (2×750 mg Trilisate®tablets) and naltrexone oral solution (placebo), and HYIR/APAP (2tablets of Vicodin ES®) and naltrexone oral solution (placebo). Alltreatments were administered under fasted conditions. A 48-hour washoutperiod occurred between doses. Subjects were randomly assigned to fourtreatment sequences of the four treatment groups. Subjects reported tothe testing facility the evening prior to the first dose and remainedconfined there until completion of the 24-hour post-dose assessment ofthe last dose. Safety measurements consisted of reports of adverseevents, vital signs, abnormal laboratory values, abnormal physicalexamination and ECG results. Pharmacodynamic parameters (pupil size andModified Specific Drug Effect Questionnaire) were also assessed.

[0171] Test Treatments

[0172] The four treatments were as follows:

[0173] Hydrocodone immediate-release tablets (2×7.5 mg) and naltrexoneoral solution 3.2 mg.

[0174] Hydrocodone immediate-release tablets (2×7.5 mg) and naltrexoneoral solution 6.4 mg.

[0175] Hydrocodone immediate-release comparator tablets and placebonaltrexone oral solution.

[0176] Placebo hydrocodone immediate-release tablets (2×7.5 mg) andplacebo naltrexone oral solution.

[0177] Test Products

[0178] The products evaluated in this study include Vicodin ES®(hydrocodone bitartrate 7.5 mg and acetaminophen 750 mg, KnollPharmaceuticals), Trilisate® (choline magnesium trisalicylate 750 mg,Purdue Frederick) which served as the comparator, and naltrexone powder.Vicodin ES® was selected as the active treatment since the acetaminophenportion within this product is expected to have no effect on the centralnervous system or pupillary measurement. Trilisate was selected to beused as the “comparator” since its physical appearance is similar toVicodin ES® and it has no effect on the central nervous system orpupillary measurement. Naltrexone powder formulation was selected ratherthan the commercially approved tablet formulation (Revia® 50 mg tablets,DuPont) to improve the overall precision in the preparation of the oralsolution. An on-site research pharmacist reconstituted the oral solutionfrom the naltrexone powder in a sterile environment utilizingappropriate pharmaceutical techniques. Naltrexone powder (MallinckrodtChemical) was used to formulate the naltrexone solution. Individualstock solutions of naltrexone were prepared using a modification of themethod proposed by Tsang and Holtsman. Tsang B K, Holtsman R. “RoomTemperature Stability of Liquid Naltrexone.” Anesthesiology1995:83:A864, hereby incorporated by reference. Immediately prior (<60minutes) to each dosing period, a naltrexone stock solution was preparedby weighing out 32 mg and 64 mg of naltrexone powder. Each of theseportions was dissolved in 50 rnL of distilled water and 50 mL of simplesyrup, NF for a vinal volume of 100 mL. The concentration of the finalsolutions was 0.32 mg/mL (32 mg/100 mL) and 0.64 mg/mL (64 mg/100 mL),respectively. These concentrations allowed the same volume (10 mL) ofnaltrexone oral solution to be administered during each dosing period.The naltrexone oral solution placebo was prepared in the same vehicle asthe active solution. The addition of a bittering agent, Bitterguard(denatonium benzoate, NF) powder, was added to provide a taste similarto the active solution.

[0179] Pharmacodynamic Measurements

[0180] a. Pupil Size—Measured by Pupillometry

[0181] Pupillary diameter measurements were made with the Polaroid CU-5camera with a 75 mm lens and built-in electronic ring flash usingPolacolor ER 669 instant pack film.12. This method has become acceptedas a safe and accurate way to study pupils and is commonly regarded asbeing second only to the infrared television pupillometric technique (amore versatile and sophisticated, but also much more expensive andcumbersome, method). The Polaroid CU-5 method is said to be accurate towithin 0.1 millimeters. See, Czarnecki J S, Pilley S F, Thompson H S.“The Use of Photography in the Clinical Evaluation of Unequal Pupils.”Canad J Ophthal 1979;14:297-302; hereby incorporated by reference.

[0182] Pupil diameters were measured as follows: The camera was modifiedby covering two small sections of the ring flash at 3 and 9 o'clock sothat the corneal reflection of the flash does not obscure the horizontalpupillary margin. The camera was centered in front of the subject's facewith 3 inch frame against the lateral orbital rims and the eyesoccupying the very top of the field (to minimize upgaze). The subjectwas asked to look just over the camera body and to fixate on anon-accommodative target in the distance, thereby minimizing the nearreflex. With the volunteer fixing in the distance, the photo was taken.All photographs were taken in constant ambient light. The pupillarylatency was such that the flash will not affect pupillary diameter.Tonic constriction of the pupil after the flash does occur, but is ofshort duration; therefore, it did not interfere with the measurementsnecessary for this trial. See, Smith S A, Dewhist R R. “A SingleDiagnostic Test for Pupillary Abnormality in Diabetic AutonomicNeuropathy.” Diabetic Medicine 1988;3:38-41; hereby incorporated byreference. Development of the print for the recommended length of time(approximately one (1) minute, varying with ambient temperature) willproduce a one-to-one photograph of the volunteer's midface, with thepupils at the top of the print. Horizontal pupillary diameter is thenmeasured using a simple plus magnifier with a built-in reticulecalibrated to 0.1 millimeter. Only the left eye was used to measurepupillary effects at each time period specified in the protocol.

[0183] b. A Modified Specific Drug Effect Questionnaire.

[0184] The questionnaire is a modification of the 22 item questionnaireused by Jasinski and Preston. See, Jasinski D R. “Assessment of theAbuse Potential of Morphine-Like Drugs (methods used in man).” In:DrugAddiction I (Martin, W. R., ed.), 1997:197-258. Springer-Verlag, NewYork; Preson K L, Jasinski D R, Testa M. “Abuse Potential andPharmacological Comparison of Tramadol and Morphine.” Drug and AlcoholDependence 1991;27:7-17; both of which are hereby incorporated byreference. The present questionnaire consisted of 10 items rated by thesubject 10 minutes prior to blood sampling. The item is related to signsof opiate agonist drugs and was as follows:

[0185] Subject questions: 1) do you feel any effects from the drugs?, 2)does your skin feel itchy?, 3) do you feel relaxed?, 4) do you feelsleepy?, 5) do you feel drunk?, 6) do you feel nervous?, 7) do you feelfull of energy?, 8) do you feel you need to talk?, 9) do you feel sickto your stomach?, 10) do you feel dizzy? The subject then rated the itemby placing a vertical mark along a 100 mm visual analog scale (VAS)anchored on one end by “not at all” and at the other end by “an awfullot”.

[0186] Pupil size of the left eye made at baseline (within 30 minutesprior to dosing), and at 0.5, 1, 2, 4, 6, 9 and 12 hours post-dose wasmeasured, and the subject rated drug effect scores as measured on avisual analog scale for the Modified Specified Drug Effect Questionnaire(“MSDEQ”) at baseline, and at 0.5, 1, 2, 4, 6, 9 and 12 hours post-dose.

[0187] Separate graphs for the eleven responses (NSDEQ questions andpupillary diameter measurement) versus naltrexone dose were visually andstatistically examined to determine the nominally effective dose ofnaltrexone in combination with the hydrocodone dose used in the study.

[0188] The adverse events reported were those commonly associated withthe administration of opioid analgesics, and most were classified as“mild”. No serious adverse events or deaths occurred, and no patientswere discontinued from the study secondary to adverse events.

[0189] Results are presented in FIGS. 1 and 2.

[0190]FIG. 1 shows the naltrexone antagonism of hydrocodone-induced VAS(Visual Analog Scale) “drug effect”. This refers to the first questionof the Modified Specific Drug Effect Questionnaire which asked thesubjects “do you feel any effects of the drug?”. The results suggestthat there is a dose-response effect for naltrexone; increasing the doseof naltrexone decreased the VAS “drug effect” of hydrocodone. The 6.4-mgdose of naltrexone antagonized the effects of a 15-mg dose ofhydrocodone to a greater degree than the 3.2-mg naltrexone dose. Theopioid effect of hydrocodone was not completely blocked by the 6.4-mgnaltrexone dose.

[0191]FIG. 2 shows the naltrexone antagonism of hydrocodone-inducedpupillary constriction. These results also suggest a dose-responseeffect for naltrexone; increasing the dose of naltrexone caused lesspupillary constriction in subjects who had received hydrocodone 15 mg.The 6.4-mg naltrexone dose antagonized hydrocodone-induced pupillaryconstriction to a greater degree than the 3.2-mg naltrexone dose. Thepupillary constriction of hydrocodone was not completely blocked by the6.4-mg naltrexone dose. The least amount of pupillary constrictionoccurred in the placebo-group. The hydrocodone plus naltrexoneplacebo-group experienced the most pupillary constriction, andtherefore, had the lowest measurements for pupillary diameter.

Example 2

[0192] In Example 2, a ten period, randomized, crossover, single-blindstudy evaluating the ratio of oral naltrexone to oral hydrocodone thatwould nominally minimize the opioid agonist effects was conducted innormal, healthy, female volunteers. Twenty-one subjects enrolled in thestudy, and 16 completed the study. The ten treatments included HYIR/APAP(2 tablets of hydrocodone 7.5 and acetaminophen 750 mg per tablet,Vicodin ES®) with the following doses of naltrexone oral solution: 0.4mg/10 mL, 0.8 mg/10 mL, 1.6 mg/10 mL, 3.2 mg/10 mL, 4.8 mg/10 mL, 6.4mg/10 mL, 9.6 mg/10 mL, 12.8 mg/10 mL, and placebo naltrexone oralsolution, as well as hydrocodone immediate-release comparator tablets(2×750 mg Trilisate® tablets) with placebo naltrexone oral solution. Alltreatments were administered under fasted conditions. A 48-hour washoutperiod occurred between doses. Subjects were randomly assigned to tentreatment sequences of the ten treatment groups. Subjects reported tothe testing facility the evening prior to the first dose and remainedconfined there until completion of the 24-hour post-dose assessment ofthe last dose. Safety measurements consisted of reports of adverseevents, vital signs, abnormal laboratory values, abnormal physicalexamination and ECG results. Plasma hydrocodone, naltrexone and6-β-naltrexol levels were obtained, and pharmacokinetic values will becalculated and analyzed. Pharmacodynamic parameters (pupil size andModified Specific Drug Effect Questionnaire) were also assessed.

[0193] Dosing Regimen

[0194] The dosing regimen was as follows:

[0195] Hydrocodone immediate-release comparator (placebo) tablets wereadministered with 10 mL naltrexone oral solution (placebo) atapproximately 08:00 on the dosing day in Periods 1 through 10 followingan 8-hour fast. The fast continued for an additional four (4) hourspost-dose;

[0196] Hydrocodone immediate-release tablets (2×7.5 mg) wereadministered with 10 mL naltrexone oral solution (placebo) atapproximately 08:00 on the dosing day in Periods I through 10 followingan 8-hour fast. The fast continued for an additional four (4) hourspost-dose;

[0197] Hydrocodone immediate-release tablets (2×7.5 mg) wereadministered with 10 mL naltrexone oral solution (0.4 mg) atapproximately 08:00 on the dosing day in Periods 1 through 10 followingan 8-hour fast. The fast continued for an additional four (4) hourspost-dose;

[0198] Hydrocodone immediate-release tablets (2×7.5 mg) wereadministered with 10 mL naltrexone oral solution (0.8 mg) atapproximately 08:00 on the dosing day in Periods 1 through 10 followingan 8-hour fast. The fast continued for an additional four (4) hourspost-dose;

[0199] Hydrocodone immediate-release tablets (2×7.5 mg) wereadministered with 10 mL naltrexone oral solution (1.6 mg) atapproximately 08:00 on the dosing day in Periods 1 through 10 followingan 8-hour fast. The fast continued for an additional four (4) hourspost-dose;

[0200] Hydrocodone immediate-release tablets (2×7.5 mg) wereadministered with 10 mL naltrexone oral solution (3.2 mg) atapproximately 08:00 on the dosing day in Periods 1 through 10 followingan 8-hour fast. The fast continued for an additional four (4) hourspost-dose;

[0201] Hydrocodone immediate-release tablets (2×7.5 mg) wereadministered with 10 mL naltrexone oral solution (4.8 mg) atapproximately 08:00 on the dosing day in Periods 1 through 10 followingan 8-hour fast. The fast continued for an additional four (4) hourspost-dose;

[0202] Hydrocodone immediate-release tablets (2×7.5 mg) wereadministered with 10 mL naltrexone oral solution (6.4 mg) atapproximately 08:00 on the dosing day in Periods 1 through 10 followingan 8-hour fast. The fast continued for an additional four (4) hourspost-dose;

[0203] Hydrocodone immediate-release tablets (2×7.5 mg) wereadministered with 10 mL naltrexone oral solution (9.6 mg) atapproximately 08:00 on the dosing day in Periods 1 through 10 followingan 8-hour fast. The fast continued for an additional four (4) hourspost-dose;

[0204] Hydrocodone immediate-release tablets (2×7.5 mg) wereadministered with 10 mL naltrexone oral solution (12.8 mg) atapproximately 08:00 on the dosing day in Periods 1 through 10 followingan 8-hour fast. The fast continued for an additional four (4) hourspost-dose.

[0205] The subjects observed an 8 hour fast preceding and fasted forfour (4) hours following each dose administration of the assigned drugon each dosing day. A baseline blood sample (for Plasma Hydrocodone,Naltrexone and 6-β-naltrexol) was obtained prior to dosing (within 30minutes) administration of initial dose (0 hr) and at 0.5, 1, 2, 4, 6and 9 hours post-dose. All samples were collected within ± 2 minute ofthe scheduled time. Measurements of the following pharmacodynamicparameters were made just prior to blood sampling at baseline (within 30minutes prior to dosing), and at 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr and 9 hrpost-dose.

[0206] Immediately prior to each dosing period, 8 individual naltrexonestock solutions were prepared by weighing out 4, 8, 16, 32, 48, 64, 96,and 1.28 mg of naltrexone powder. Each of these portions were dissolvedin 50 ml of distilled water and 50 ml of simple syrup. The finalsolution was 100 mL at a concentration of 0.04, 0.08, 0.16, 0.32, 0.48,0.96, and 1.28 mg/mL. These concentrations allowed the same volume (10ml) of naltrexone solution to be administered during each dosing period.The naltrexone placebo solution was be prepared in the same vehicles asthe active solution. The addition of a bittering agent, BitterguardPowder (denatonium benzoate), was added to provide a taste similar tothe active solution.

[0207] Pharmacodynamic Measurements

[0208] Pharmacodynamic measurements for Example 2 were obtained inaccordance with the procedures set forth with respect to Example 1above.

[0209] The mean “drug effect” VAS score and pupil diameter over time foreach of the treatments are presented in FIGS. 3 and 4, respectively. Ingeneral, the single-dose administration of hydrocodone immediaterelease/ acetaminophen (“HYIR/APAP”) with increasing doses of naltrexone(range 0 mg - 12.8 mg) resulted in an overall decrease in “drug effect”VAS score and decrease in pupillary constriction. FIGS. 5 and 6 presentthe corresponding mean maximum “drug effect” VAS score (±95% CI) andmean minimum pupil diameter (±95% CI) versus the log from each of thenaltrexone doses. Both figures suggest a dose-response relationship withthe pupil effect demonstrating a greater dose-response relationshipcompared to the “drug effect” VAS response.

[0210] The results suggest that even with the inclusion of 0.4 mgnaltrexone, there was a diminution of pharmacologic effects of the doseof hydrocodone. Approximately 0.4 mg of naltrexone minimally antagonizedthe 15 mg hydrocodone dose. Dosages above naltrexone 0.4 mg began toshow increasing diminution of the effect of the hydrocodone dose.

[0211] The adverse events reported were those commonly associated withthe administration of opioid analgesics, and most were classified as“mild”. A total of five subjects (5/21) discontinued the study. Threesubjects discontinued due to adverse events. Two of these subjectsexperienced adverse events which were classified as non-serious. Onesubject developed anemia which was classified as serious, and requirediron therapy. Another two subjects were discontinued from the studybecause their physicians felt there was information in their medicalhistory that did not make it possible for them to participate. No deathsoccurred in this study.

[0212] In general, the single-dose administration of 15 mg hydrocodoneimmediate-release tablets with increasing doses of naltrexone oralsolution (range 0 mg - 12.8 mg) resulted in an overall decrease in “drugeffect” VAS score and an increase in pupil diameter.

[0213] EXAMPLE 3

[0214] Example 3 presents the results of a study evaluating precipitatedwithdrawal in morphine dependent volunteers receiving hydrocodoneimmediate-release tablets and naltrexone oral solution. The study was asingle-blind, single-dose, placebo-controlled naltrexone dose ascendingstudy in subjects physically dependent on opioids. The experimentalsubjects (5) were opioid-dependent as determined by Narcan challenge,Addiction Severity Index scores, physical examination, observation andurine drug screen results, and were not currently seeking treatment fortheir addiction. To evaluate precipitated withdrawal following thecoadministration of hydrocodone immediate release and naltrexone, a 30mg dose of hydrocodone immediate release was selected to simulate a doselevel used by individuals who abuse hydrocodone. This is also a dosewhich is considered to be equianalgesic to other commonly used opioidsin opioid naive patients. The relative analgesic potency of hydrocodoneis believed to be similar to that of oxycodone and about two times thatof oral morphine.

[0215] Test Treatments

[0216] The treatments were as follows:

[0217] Hydrocodone/acetaminophen immediate-release (HYIR/APAP) tablets30 mg (Lortab® 3×10 mg) and increasing doses of naltrexone oralsolutions 0, 0.25 mg, 0.5 mg, 1.0 mg and 2.0 mg.Hydrocodone/acetaminophen immediate-release (HYIR/APAP) tablets 30 mg(Lortab® 3×10 mg) and naltrexone placebo oral solution. The naltrexoneoral solution and placebo solution were prepared in accordance withExamples 1-2.

[0218] The subjects were stabilized for 5 days by administering 15 mgmorphine sulphate i.m. at regular intervals: 6 and 10 A.M., and 4 and 10P.M. daily. Fifteen mg morphine sulphate i.m. is equivalent to 30 mghydrocodone given orally. The study medications were administered afterstabilization at 10 AM on study medication dosing days, and observationswere made over the next six hours. After six hours, if precipitatedwithdrawal was not observed, the administration of morphine sulfate 15mg intramuscularly resumed with the 4 PM dose. The subjects werestabilized 48 hours before the next study drug administration. Followingeach treatment (1-4), if precipitated withdrawal was not observed, thesubject received study medication from the next treatment in thefollowing ascending order:

[0219] Treatment No. 1: HYIR/APAP tablets 30 mg (Lortab® 3×10 mg)administered with placebo naltrexone (10 mL) oral solution atapproximately 10:00 on the dosing day following an 8-hour fast. The fastcontinued for an additional four (4) hours post-dose.

[0220] Treatment No. 2: HYIR/APAP tablets 30 mg (Lortab® 3×10 mg)administered with 0.25 mg naltrexone (10 mL) oral solution atapproximately 10:00 on the dosing day following an 8-hour fast. The fastcontinued for an additional four (4) hours post-dose.

[0221] Treatment No. 3: HYIR/APAP tablets 30 mg (Lortab® 3×10 mg)administered with 0.5 mg naltrexone (10 mL) oral solution atapproximately 10:00 on the dosing day following an 8-hour fast. The fastcontinued for an additional four (4) hours post-dose.

[0222] Treatment No. 4: HYIR/APAP tablets 30 mg (Lortab® 3×10 mg)administered with 1.0 mg naltrexone (10 mL) oral solution atapproximately 10:00 on the dosing day following an 8-hour fast. The fastcontinued for an additional four (4) hours post-dose.

[0223] Treatment No. 5: HYIR/APAP tablets 30 mg (Lortab® 3×10 mg)administered with 2.0 mg naltrexone (10 mL) oral solution atapproximately 10:00 on the dosing day following an 8-hour fast. The fastcontinued for an additional four (4) hours post-dose.

[0224] Blood samples were collected at 0.5 hours pre-dose, and at 0.5,1, 2, 4 and 6 hours post-dose. Pupil diameter measurements were obtainedusing a Pupilscan pupillometer and recorded in millimeters to thenearest millimeter. There was a 48 hour washout period following eachtest period. Four subjects completed the study, one subject wasterminated. The effect of naltrexone was a slight abstinence (symptomsof withdrawal) at 1 and 2 mg.

[0225] The protocol was amended and twelve experimental subjectsparticipated in the protocol, which was identical to the study outlinedabove except for the increased ratio of naltrexone. Naltrexone doses inthe revised protocol were 0, 1, 2, 4 and 8 mg. Eight of the experimentalsubjects completed the study, while four withdrew.

[0226] Vital signs for each subject were monitored, and subjects weremonitored for signs and symptoms of opioid withdrawal. Withdrawal signsinclude stuffiness or running nose, tearing, yawning, sweating, tremors,vomiting, piloerection, mydriasis, irritability and restlessness.Withdrawal symptoms include feeling of temperature change, joint, boneor muscle pain, abdominal cramps, skin crawling, nausea, and thesubject's reporting the subjective experience of the aforementionedsymptoms.

[0227] To provide a measure of the subjective experience of the drugcombination, the subjects answered questionnaires throughout the studyperiod. The responses to questions were graded on the Visual AnalogScale as described in Example 1. The subjective experiences that wereassessed were as follows: like/dislike of the drug, ability to perceivedrug effect, sweating, restlessness, shakiness, watery eyes, gooseflesh,stomach upset, nasal congestion, sleepiness, cold, hot, muscle ache,tenseness or relaxation, confusion, fearfulness, irritability,talkativeness, sensations of withdrawal, sensations of sickness. Thesubjects were also observed for the following symptoms: yawning,scratching, relaxed, nasal congestion, irritability, withdrawal. Inaddition, blood pressure, pulse rate, respiration rate, pupil size andbody temperature were monitored.

[0228] The data for five of the subjects are presented below. FIGS. 7A-Cillustrate the mean scores for subjective perception of hydrocodone fromthe questionnaires, plotted as a function of time post administrationand as a function of naltrexone dose. FIG. 7A illustrates the subjects'ability to feel the effect of hydrocodone in the presence of varyingamounts of naltrexone. FIGS. 7B and 7C illustrate the subjects'favorableor unfavorable subjective experiences of hydrocodone in the presence ofvarying amounts of naltrexone, respectively.

[0229]FIGS. 8A and B illustrate the mean scores for subjectiveperception of the effects of hydrocodone, plotted as a function of timepost administration and as a function of naltrexone dose. FIG. 8Aillustrates the subjects' perception of withdrawal from the effect ofhydrocodone in the presence of varying amounts of naltrexone. FIG. 8Billustrates the subjective experience of illness in the presence ofvarying amounts of naltrexone. FIG. 9A illustrates the effect on pupilsize of hydrocodone in the presence of varying amounts of naltrexone.FIG. 9B illustrates the apparent extent of withdrawal from the effect ofhydrocodone in the presence of varying amounts of naltrexone, from theperspective of the observer.

[0230] FIGS. 10A-C present the areas under the curves presented in FIGS.7A-C, integrated over the 6 hour observation period, as a function ofnaltrexone dose, and the 95% confidence levels for the placebo responseof naltrexone (30 mg hydrocodone, 0 mg naltrexone). FIG. 10A illustratesthat up to 8 mg naltrexone does not abolish the ability of the subjectto perceive the effect of hydrocodone: the experimentally determined AUC(0 to 6 hours) observed for each naltrexone dose lies wholly within the95% confidence limits for the naltrexone placebo response. FIG. 10Billustrates the AUC (0 to 6 hours) for the subjects' favorablesubjective experience to hydrocodone as a function of naltrexone dose.FIG. 10B illustrates that the favorable subjective experience isdecreased for>1 mg naltrexone, that is, the experimentally determinedAUC (0 to 6 hours) decreased below the 95% confidence limits fornaltrexone placebo at approximately 1 mg naltrexone. FIG. 10Cillustrates that the unfavorable subjective experience is increasedfor>1 mg naltrexone, that is, the experimentally determined AUC (0 to 6hours) increased above the 95% confidence limits for naltrexone placeboat approximately 1 mg naltrexone.

[0231] FIGS. 11A-C present the areas under the curves presented in FIGS.8A-B and FIG. 9A, integrated over the 6 hour observation period, as afunction of naltrexone dose, and the 95% confidence levels for theplacebo response of naltrexone (30 mg hydrocodone, 0 mg naltrexone).FIG. 11A illustrates the AUC (0 to 6 hours) for the subjectiveexperience of illness in the presence of varying amounts of naltrexone.FIG. 11A demonstrates that doses of naltrexone greater thanapproximately 0.75 mg result in the subjective experience of withdrawal:the experimentally determined AUC (0 to 6 hours) observed in FIG. 8A foreach naltrexone dose increases above the 95% confidence limits for thenaltrexone placebo response at approximately 0.75 mg naltrexone. FIG.11B illustrates the AUC (0 to 6 hours) for the subjects' perception ofillness in the presence of varying amounts of naltrexone. FIG. 11Bdemonstrates that doses of naltrexone greater than approximately 0.75 mgresult in the subjective experience of illness: the experimentallydetermined AUC (0 to 6 hours) observed in FIG. 8B for each naltrexonedose increases above the 95% confidence limits for the naltrexoneplacebo response at approximately 0.75 mg naltrexone. FIG. 11Cillustrates the AUC (0 to 6 hours) of the experimentally determinedchange in pupil size as a function of naltrexone dose. FIG. 11Cdemonstrates that up to 8 mg naltrexone does not abolish the miosiseffect of hydrocodone: the experimentally determined AUC (0 to 6 hours)observed in FIG. 9A for each naltrexone dose lies wholly within the 95%confidence limits for the naltrexone placebo response.

[0232] The clinical study demonstrates that hydrocodone, in combinationwith naltrexone, has an onset of<0.5 hours, peaks within 0.5 to 1 hourand is markedly diminished within 3 to 4 hours. A shallow dose-responsecurve was observed. The addition of naltrexone decreased the favorablesubjective experience of hydrocodone, increased the subjectiveexperience of dislike for hydrocodone and increased the subjectiveexperience of sickness and withdrawal from the effects of hydrocodone.These experiences are clearly aversive.

[0233] While the invention has been described and illustrated withreference to certain preferred embodiments thereof, those skilled in theart will appreciate that obvious modifications can be made hereinwithout departing from the spirit and scope of the invention. Suchvariations are contemplated to be within the scope of the appendedclaims.

What is claimed is:
 1. An oral dosage form, comprising an orallytherapeutically effective amount of an opioid agonist, and an opioidantagonist, the ratio of opioid antagonist to opioid agonist providing acombination product which is analgesically effective when thecombination is administered orally, but which is aversive in physicallydependent human subjects when administered at the same dose or at ahigher dose than the usually prescribed dose of the opioid agonist. 2.The oral dosage form of claim 1, wherein the amount of antagonistincluded in the oral dosage form causes an aversive experience in aphysically dependent addict taking about 2-3 times the usuallyprescribed dose of the opioid.
 3. The oral dosage form of claim 1,wherein the opioid agonist is hydrocodone and the antagonist isnaltrexone.
 4. The oral dosage form of claim 3, wherein the ratio ofnaltrexone to hydrocodone is from about 0.03:1 to about 0.27:1.
 5. Theoral dosage form of claim 3, wherein the ratio of naltrexone tohydrocodone is from about 0.05:1 to about 0.20:1.
 6. The oral dosageform of claim 1, wherein the opioid agonist or analgesic is selectedfrom the group consisting of morphine, hydromorphine, hydrocodone,oxycodone, codeine, levorphanol, meperidine, methadone, and mixturesthereof.
 7. The oral dosage form of claim 1, further comprising anadditional non-opioid drug selected from the group consisting of anNSAID, a COX-2 inhibitor, acetaminophen, aspirin, an NMDA receptorantagonist, a drug that blocks a major intracellular consequence ofNMDA-receptor activation, an antitussive, an expectorant, adecongestant, an antihistamine and mixtures thereof.
 8. The oral dosageform of claim 1, further comprising one or more pharmaceuticallyacceptable inert excipients.
 9. The oral dosage form of claim 6, whereinsaid opioid antagonist is selected from the group consisting ofnaltrexone, naloxone, nalmephene, cyclazocine, levallorphan, andmixtures thereof.
 10. The oral dosage form of claim 6, wherein saidopioid antagonist is naltrexone.
 11. The oral dosage form of claim 1,further comprising a sustained release carrier which imparts sustainedrelease properties to said opioid agonist.
 12. The oral dosage form ofclaim 1, wherein said opioid antagonist is naltrexone and said opioidagonist is oxycodone, wherein the ratio of naltrexone to oxycodone isfrom about 0.037:1 to about 0.296:1.
 13. The oral dosage form of claim1, wherein said opioid antagonist is naltrexone and said opioid agonistis codeine, wherein the ratio of naltrexone to codeine is from about0.005:1 to about 0.044:1.
 14. The oral dosage form of claim 1, whereinsaid opioid antagonist is naltrexone and said opioid agonist ishydromorphone, wherein the ratio of naltrexone to hydromorphone is fromabout 0.148:1 to about 1.185:1.
 15. The oral dosage form of claim 1,wherein said opioid antagonist is naltrexone and said opioid agonist islevorphanol, wherein the ratio of naltrexone to levorphanol is fromabout 0.278:1 to about 2.222:1.
 16. The oral dosage form of claim 1,wherein said opioid antagonist is naltrexone and said opioid agonist ismeperidine, wherein the ratio of naltrexone to meperidine is from about0.0037:1 to about 0.0296:1.
 17. The oral dosage form of claim 1, whereinsaid opioid antagonist is naltrexone and said opioid agonist ismethadone, wherein the ratio of naltrexone to methadone is from about0.056:1 to about 0.444:1.
 18. The oral dosage form of claim 1, whereinsaid opioid antagonist is naltrexone and said opioid agonist ismorphine, wherein the ratio of naltrexone to morphine is from about0.018:1 to about 0.148:1.
 19. The oral dosage form of claim 1, whereinsaid opioid antagonist is naltrexone and said opioid agonist isoxycodone, wherein the ratio of naltrexone to oxycodone is from about0.056:1 to about 0.222:1.
 20. The oral dosage form of claim 1, whereinsaid opioid antagonist is naltrexone and said opioid agonist is codeine,wherein the ratio of naltrexone to codeine is from about 0.0083:1 toabout 0.033:1.
 21. The oral dosage form of claim 1, wherein said opioidantagonist is naltrexone and said opioid agonist is hydromorphone,wherein the ratio of naltrexone to hydromorphone is from about 0.222: 1to about 0.889:1.
 22. The oral dosage form of claim 1, wherein saidopioid antagonist is naltrexone and said opioid agonist is levorphanol,wherein the ratio of naltrexone to levorphanol is from about 0.417:1 toabout 1.667:1.
 23. The oral dosage form of claim 1, wherein said opioidantagonist is naltrexone and said opioid agonist is meperidine, whereinthe ratio of naltrexone to meperidine is from about 0.0056:1 to about0.022:1.
 24. The oral dosage form of claim 1, wherein said opioidantagonist is naltrexone and said opioid agonist is methadone, whereinthe ratio of naltrexone to methadone is from about 0.083:1 to about0.333:1.
 25. The oral dosage form of claim 1, wherein said opioidantagonist is naltrexone and said opioid agonist is morphine, whereinthe ratio of naltrexone to morphine is from about 0.028:1 to about0.111:1.
 26. A method of preventing oral abuse of an oral opioidformulation, comprising preparing an oral dosage form which comprises anorally analgesically effective amount of an opioid agonist andincorporating therein an opioid antagonist in a ratio to said opioidagonist such that the oral dosage form is analgesically effective whenadministered orally, but is aversive in physically dependent humansubjects when administered at the same dose or at a higher dose than theusually prescribed dose of the opioid agonist.
 27. The method of claim26, wherein the amount of antagonist included in the oral dosage formcauses an aversive experience in physically dependent addicts takingabout 2-3 times the usually prescribed dose of the opioid.
 28. Themethod of claim 26, wherein the opioid agonist is hydrocodone and theantagonist is naltrexone.
 29. The method of claim26, wherein the ratioof naltrexone to hydrocodone is from about 0.03:1 to about 0.27:1. 30.The method of claim 26, wherein the ratio of naltrexone to hydrocodoneis from about 0.05:1 to about 0.20:1.
 31. The method of claim 26, hereinthe opioid agonist or analgesic is selected from the group consisting ofmorphine, hydromorphine, hydrocodone, oxycodone, codeine, levorphanol,meperidine, methadone, and mixtures thereof and the opioid antagonist isselected from the group consisting of naltrexone, naloxone, nalmephene,cyclazocine, levallorphan, and mixtures thereof.
 32. The method of claim26, wherein the opioid antagonist is naltrexone and the opioid agonistis selected from the group consisting of hydrocodone in analtrexone:hydrocodone ratio from about 0.03:1 to about 0.27:1;oxycodone in a naltrexone/oxycodone ratio from about 0.037:1 to about0.296:1; codeine in a naltrexone/codeine ratio from about 0.005:1 toabout 0.044: 1; hydromorphone in a naltrexone/ hydromorphone ratio fromabout 0.148:1 to about 1.185:1; levorphanol in a naltrexone/levorphanolratio from about 0.278:1 to about 2.222:1; meperidine in analtrexone/meperidine ratio from about 0.0037:1 to about 0.0296:1;methadone in a naltrexone/methadone ratio from about 0.056:1 to about0.444:1; and morphine in a naltrexone/ morphine ratio from about 0.018:1to about 0.148:1.
 33. The method of claim 26, wherein the opioidantagonist is naltrexone and the opioid agonist is selected from thegroup consisting of hydrocodone in a naltrexone:hydrocodone ratio fromabout 0.05:1 to about 0.20:1; oxycodone in a naltrexone/oxycodone ratiofrom about 0.056:1 to about 0.222:1; codeine in a naltrexone/codeineratio from about 0.0083:1 to about 0.033:1; hydromorphone in analtrexone/hydromorphone ratio from about 0.222:1 to about 0.889:1;levorphanol in a naltrexone/levorphanol ratio from about 0.417:1 toabout 1.667:1; meperidine in a naltrexone/meperidine ratio from about0056:1 to about 0.022:1; methadone in a naltrexone/methadone ratio fromabout 0.083:1 to about 0.333:1; and morphine in a naltrexone/ morphineratio from about 0.028:1 to about 0.111:1.
 34. The method of claim 32,further comprising incorporating into said oral dosage form anadditional non-opioid drug selected from the group consisting of anNSAID, a COX-2 inhibitor, acetaminophen, aspirin, an NMDA receptorantagonist, a drug that blocks a major intracellular consequence ofNMDA-receptor activation, an antitussive, an expectorant, adecongestant, an antihistamine and mixtures thereof.
 35. The method ofclaim 26, further comprising preparing said oral dosage form with asustained release carrier such that the dosage form is administrable ona twice-a-day or on a once-a-day basis.